Trpv4 antagonists

ABSTRACT

The present invention relates to pyrrolidine sulfonamide analogs, pharmaceutical compositions containing them and their use as TRPV4 antagonists.

FIELD OF THE INVENTION

The present invention relates to pyrrolidine sulfonamide analogs,pharmaceutical compositions containing them and their use as TRPV4antagonists.

BACKGROUND OF THE INVENTION

TRPV4 is a member of the Transient Receptor Potential (TRP) superfamilyof cation channels and is activated by heat, demonstrating spontaneousactivity at physiological temperatures (Guler et al., 2002. J Neurosci22: 6408-6414). Consistent with its polymodal activation property TRPV4is also activated by hypotonicity and physical cell stress/pressure(Strotmann et al., 2000. Nat Cell Biol 2: 695-702), through a mechanisminvolving phospholipase A2 activation, arachidonic acid andepoxyeicosatrienoic acid generation (Vriens et al., 2004. Proc Natl AcadSci USA 101:396-401). In addition, amongst other mechanisms proposed,tyrosine kinase activity, as well as protein kinase A and C, may alsoregulate TRPV4 (Wegierski et al., 2009. J Biol Chem. 284: 2923-33; Fanet al., 2009. J Biol Chem 284: 27884-91).

Heart failure results in the decreased ability of the left ventricle topump blood into the peripheral circulation as indicated by a reducedejection fraction and/or left ventricular dilation. This increases theleft ventricular end diastolic pressure resulting in enhanced pulmonaryblood pressures. This places the septal barrier, which separates thecirculatory aqueous environment and the alveolar airspaces of the lung,at risk. Increased pulmonary pressure results in the flow of fluid fromthe pulmonary circulation into the alveolar space resulting in lungedema/congestion, as is observed in patients with congestive heartfailure.

TRPV4 is expressed in the lung (Delany et al., 2001. Physiol. Genomics4: 165-174) and its level of expression is up-regulated in individualswith congestive heart failure (Thorneloe et al., 2012. Sci Transl Med 4:159ra148). TRPV4 has been shown to mediate Ca²⁺ entry in isolatedendothelial cells and in intact lungs (Jian et al., 2009. Am J RespirCell Mol Biol 38: 386-92). Endothelial cells are responsible for formingthe capillary vessels that mediate oxygen/carbon dioxide exchange andcontribute to the septal barrier in the lung. Activation of TRPV4channels results in contraction of endothelial cells in culture andcardiovascular collapse in vivo (Willette et al., 2008. J Pharmacol ExpTher 325: 466-74), at least partially due to the enhanced filtration atthe septal barrier evoking lung edema and hemorrage (Alvarez et al.,2006. Circ Res 99: 988-95). Indeed, filtration at the septal barrier isincreased in response to increased vascular and/or airway pressures andthis response is dependent on the activity of TRPV4 channels (Jian etal., 2008. Am J Respir Cell Mol Biol 38:386-92). Consistent with theseobservations, TRPV4 antagonists prevent and resolve pulmonary edema inheart failure models (Thorneloe et al., 2012. Sci Transl Med 4:159ra148). Overall this suggests a clinical benefit of inhibiting TRPV4function in the treatment of acute and/or chronic heart failureassociated lung congestion.

Additional benefit is suggested in inhibiting TRPV4 function inpulmonary-based pathologies presenting with symptoms including lungedema/congestion, infection, inflammation, pulmonary remodeling and/oraltered airway reactivity. A genetic link between TRPV4 and chronicobstructive pulmonary disorder (COPD) has recently been identified (Zhuet al., 2009. Hum Mol Genetics, 18: 2053-62) suggesting potentialefficacy for TRPV4 modulation in treatment of COPD with or withoutcoincident emphysema. Enhanced TRPV4 activity is also a key driver inventilator-induced lung injury (Hamanaka et al., 2007. Am J Physiol 293:L923-32) and it is suggested that TRPV4 activation may underliepathologies involved in acute respiratory distress syndrome (ARDS),pulmonary fibrosis (Rahaman et al., 2014. J Clin Invest 124: 5225-38),cough (Bonvini et al., 2016 J Allergy Clin Immunol 138: 249-61) andasthma (Liedtke & Simon, 2004. Am J Physiol 287: 269-71). A potentialclinical benefit for TRPV4 blockers in the treatment of sinusitis, aswell as allergic and non-allergic rhinitis is also supported (Bhargaveet al., 2008. Am J Rhinol 22:7-12).

TRPV4 has been shown to be involved in acute lung injury (ALI). Chemicalactivation of TRPV4 disrupts the alvelor septal blood barrierpotentially leading to pulmonary edema (Alvarez et al, Circ Res. 2006Oct. 27; 99(9):988-95). In animal models, TRPV4 antagonism attenuateslung damage induced by chemical agents and biological toxins such asHCl, chlorine gas, and platelet activating factor (Balakrishna et al.,2014. Am J Physiol Lung Cell Mol Physiol 307: L158-72; Morty et al.,2014. Am J Physiol Lung Cell Mol Physiol 307: L817-21; Yin et al., 2016.Am J Respir Cell Mol Biol 54: 370-83). In addition, TRPV4 is necessaryin a process known to cause or worsen ALI in humans (Hamanaka et al, AmJ Physiol Lung Cell Mol Physiol. 2007 October; 293(4):L923-32). Overallthis suggests a clinical benefit of inhibiting TRPV4 function in thetreatment of ARDS and ALI.

Furthermore, TRPV4 has in recent years been implicated in a number ofother physiological/pathophysiological processes in which TRPV4antagonists are likely to provide significant clinical benefit. Theseinclude various aspects of pain (Todaka et al., 2004. J Biol Chem 279:35133-35138; Grant et al., 2007. J Physiol 578: 715-733;Alessandri-Haber et al., 2006. J Neurosci 26: 3864-3874), genetic motorneuron disorders (Auer-Grumbach et al., 2009. Nat Genet. PMID: 20037588;Deng et al., 2009. Nat Genet PMID: 20037587; Landoure et al., 2009. NatGenet. PMID: 20037586), cardiovascular disease (Earley et al., 2005.Circ Res 97: 1270-9; Yang et al., 2006. Am. J Physiol. 290:L1267-L1276),bone related disorders [including osteoarthritis (Muramatsu et al.,2007. J. Biol. Chem. 282: 32158-67), genetic gain-of function mutations(Krakow et al., 2009. Am J Hum Genet 84: 307-15; Rock et al., 2008 NatGenet 40: 999-1003) and osteoclast differentiation (Masuyama et al.2008. Cell Metab 8: 257-65)], itch (Akiyama et al., 2016. J InvestDermatol 136: 154-60; Chen et al., 2016. J Biol Chem 291: 10252-62),stroke and disorders associated with cerebral edema (Li et al., 2013.Front Cell Neurosci 7: 17; Jie et al., 2015. Front Cell Neurosci 9:141), inflammatory bowel disorders (Vergnolle, 2014. Biochem Pharmacol89: 157-61), various diseases of the eye including glaucoma andretinopathy (Monaghan et al., 2015. PloS One 10: e0128359; Jo et al.,2016. Proc Natl Acad Sci USA 113: 3885-90), and metabolic syndromeincluding obesity and diabetes (Ye et al., 2012. Cell 151: 96-110; Duanet al., 2015. Mol Genet Genomics 290: 1357-65).

Thornelone et al., 2012. Sci Trans Med 4:159ra148; Balakrishna et al.,2014 Am J Physiol Lung Cell Mol Physiol. 307:1L158-Li72; Hilfiker etal., 2013 ACS Med. Chem. Lett. 4: 293-296; Skerratt et al., 2013 Med.Chem. Commun. 4: 244-251; Everaerts et al., 2010, Proc Natl Acad Sci USA107: 19084-19089; and Vincent et al., 2009 Biochem Biophys Res Commun389: 490-494, describe antagonists of TRPV4.

Chronic cough is highly prevalent worldwide and is highly impactful onthe quality of life for suffers, with typical cough rates of 10-50coughs per hour, during waking hours. It is hypothesized that chroniccough reflects a state of neuronal hypersensitivity involvingexaggerated spinal and cortical responses to afferent sensory signals ina manner similar to chronic pain. Activation of TRPV4 channels in vivocauses ATP release and triggers afferent sensory signals from the lungthrough binding of ATP to P2X3 channels, resulting in cough (Bonvini SJ, et al., J Allergy Clin Immunol. 2016 July; 138(1):249-261.e12). ATPlevels are increased in exhaled breath of patients with diseasesassociated with cough, for example COPD (Basoglu O K, et al., Chest.2015 August; 148(2):430-5). Recently a P2X3 anatagonist has demonstratedhigh level efficacy in reducing chronic cough and improving quality oflife scores in a phase 2 clinical trial (Abdulqawi R, et al. Lancet.2015 Mar. 28; 385(9974):1198-1205). These clinical data along with datafrom pre-clinical models suggests a role for TRPV4 receptors ingenerating cough. TRPV4 receptors are expressed in airway smooth musclecells (McAlexander M A, et al., J Pharmacol Exp Ther. 2014 April;349(1):118-25), in airway epithelial cells (Delany N S, et al., PhysiolGenomics. 2001 Jan. 19; 4(3):165-74), and in sensory neurons in thelung, including Ad-fibers from airway specific afferent neurons (BonviniS J, et al., J Allergy Clin Immunol. 2016 July; 138(1):249-261.e12).Taken together, these data suggest a potential therapeutic role forTRPV4 antagonists in cough; including acute cough, sub-acute cough andchronic cough.

SUMMARY OF THE INVENTION

In one aspect this invention provides for pyrrolidine sulfonamidecompounds of Formula (I), pharmaceutically acceptable salts thereof, andpharmaceutical compositions containing them.

In a second aspect, this invention provides for the use of the compoundsof Formula (I) as TRPV4 antagonists.

In another aspect, this invention provides for compounds of Formula (I)for use in therapy.

In another aspect, this invention provides for the use of the compoundsof Formula (I) for treating conditions associated with TRPV4 imbalance.

In yet another aspect, this invention provides for a method of treatmentof atherosclerosis, disorders related to vasogenic edema, postsurgicalabdominal edema, ocular edema, cerebral edema, local and systemic edema,fluid retention, sepsis, hypertension, inflammation, bone relateddysfunctions and congestive heart failure, pulmonary disorders, chronicobstructive pulmonary disorder, ventilator induced lung injury, highaltitude induced pulmonary edema, acute respiratory distress syndrome,acute lung injury, pulmonary fibrosis and other fibrosis-relateddisorders, sinusitis/rhinitis, asthma, COPD, cough; including acutecough, sub-acute cough and chronic cough, pulmonary hypertension,overactive bladder, cystitis, pain, motor neuron disorders, genetic gainof function disorders, amyotrophic lateral sclerosis, multiplesclerosis, cardiovascular disease, acute, chronic and polycystic kidneydisease, stroke, hydrocephalus, glaucoma, retinopathy, endometriosis,pre-term labor, dermatitis, pruritus, pruritus in liver disease, ascitesand complications of portal hypertension and liver cirrhosis, diabetes,metabolic disorder, obesity, migraine, Alzheimer's disease,pancreatitis, tumor suppression, immunosuppression, osteoarthritis,crohn's disease, colitis, diarrhea, intestinal irregularity(hyperreactivity/hyporeactivity), fecal incontinence, irritable bowelsyndrome (IBS), constipation, intestinal pain and cramping, celiacdisease, lactose intolerance, or flatulence, which method comprisesadministering to a subject, suitably a human subject, in need thereof atherapeutically effective amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof.

In yet another aspect, this invention provides for the use of thecompounds of Formula (I), and pharmaceutically acceptable salts thereof,for the treatment of atherosclerosis, disorders related to vasogenicedema, postsurgical abdominal edema, ocular edema, cerebral edema, localand systemic edema, fluid retention, sepsis, hypertension, inflammation,bone related dysfunctions and congestive heart failure, pulmonarydisorders, chronic obstructive pulmonary disorder, ventilator inducedlung injury, high altitude induced pulmonary edema, acute respiratorydistress syndrome, acute lung injury, pulmonary fibrosis,sinusitis/rhinitis, asthma, COPD, cough; including acute cough,sub-acute cough and chronic cough, pulmonary hypertension, overactivebladder, cystitis, pain, motor neuron disorders, genetic gain offunction disorders, cardiovascular disease, acute, chronic andpolycystic kidney disease, stroke, glaucoma, retinopathy, endometriosis,pre-term labor, dermatitis, pruritus, pruritus in liver disease,diabetes, metabolic disorder, obesity, migraine, pancreatitis, tumorsuppression, immunosuppression, osteoarthritis, crohn's disease,colitis, diarrhea, intestinal irregularity(hyperreactivity/hyporeactivity), fecal incontinence, irritable bowelsyndrome (IBS), constipation, intestinal pain and cramping, celiacdisease, lactose intolerance, or flatulence.

In yet another aspect, this invention provides for compounds of Formula(I), and pharmaceutically acceptable salts thereof, for use in thetreatment of atherosclerosis, disorders related to vasogenic edema,postsurgical abdominal edema, ocular edema, cerebral edema, local andsystemic edema, fluid retention, sepsis, hypertension, inflammation,bone related dysfunctions and congestive heart failure, pulmonarydisorders, chronic obstructive pulmonary disorder, ventilator inducedlung injury, high altitude induced pulmonary edema, acute respiratorydistress syndrome, acute lung injury, pulmonary fibrosis,sinusitis/rhinitis, asthma, COPD, cough; including acute cough,sub-acute cough and chronic cough, pulmonary hypertension, overactivebladder, cystitis, pain, motor neuron disorders, genetic gain offunction disorders, cardiovascular disease, acute, chronic andpolycystic kidney disease, stroke, glaucoma, retinopathy, endometriosis,pre-term labor, dermatitis, pruritus, pruritus in liver disease,diabetes, metabolic disorder, obesity, migraine, pancreatitis, tumorsuppression, immunosuppression, osteoarthritis, crohn's disease,colitis, diarrhea, intestinal irregularity(hyperreactivity/hyporeactivity), fecal incontinence, irritable bowelsyndrome (IBS), constipation, intestinal pain and cramping, celiacdisease, lactose intolerance, or flatulence.

In yet another aspect, this invention provides for the use of thecompounds of Formula (I), and pharmaceutically acceptable salts thereof,in the manufacture of a medicament for the treatment of atherosclerosis,disorders related to vasogenic edema, postsurgical abdominal edema,ocular edema, cerebral edema, local and systemic edema, fluid retention,sepsis, hypertension, inflammation, bone related dysfunctions andcongestive heart failure, pulmonary disorders, chronic obstructivepulmonary disorder, ventilator induced lung injury, high altitudeinduced pulmonary edema, acute respiratory distress syndrome, acute lunginjury, pulmonary fibrosis, sinusitis/rhinitis, asthma, COPD, cough;including acute cough, sub-acute cough and chronic cough, pulmonaryhypertension, overactive bladder, cystitis, pain, motor neurondisorders, genetic gain of function disorders, cardiovascular disease,acute, chronic and polycystic kidney disease, stroke, glaucoma,retinopathy, endometriosis, pre-term labor, dermatitis, pruritus,pruritus in liver disease, diabetes, metabolic disorder, obesity,migraine, pancreatitis, tumor suppression, immunosuppression,osteoarthritis, crohn's disease, colitis, diarrhea, intestinalirregularity (hyperreactivity/hyporeactivity), fecal incontinence,irritable bowel syndrome (IBS), constipation, intestinal pain andcramping, celiac disease, lactose intolerance, or flatulence.

The TRPV4 antagonist may be administered alone or in conjunction withone or more other therapeutic agents, eg. agents selected from the groupconsisting of endothelin receptor antagonists, angiotensin convertingenzyme (ACE) inhibitors, angiotension II receptor antagonists,vasopeptidase inhibitors, vasopressin receptor modulators, diuretics,digoxin, beta blockers, aldosterone antagonists, inotropes, NSAIDS,nitric oxide donors, calcium channel modulators, muscarinic antagonists,steroidal anti-inflammatory drugs, bronchodilators, antihistamines,leukotriene antagonist, HMG-CoA reductase inhibitors, dual non-selectivePadrenoceptor and nq-adrenoceptor antagonists, type-5 phosphodiesteraseinhibitors, and renin inhibitors.

Other aspects and advantages of the present invention are describedfurther in the following detailed description of the preferredembodiments thereof.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to compounds of Formula (I) and to the use ofcompounds of Formula (I) in the methods of the invention:

wherein:

-   -   R¹ is selected from:        -   aryl,        -   aryl substituted from 1 to 4 times by R^(a),        -   heteroaryl,        -   heteroaryl substituted from 1 to 4 times by R^(a)        -   bicycloheteroaryl, and        -   bicycloheteroaryl substituted from 1 to 4 times by R^(a);    -   R² is selected from:        -   aryl,        -   aryl substituted from 1 to 4 times by R^(b),        -   heteroaryl,        -   heteroaryl substituted from 1 to 4 times by R^(b),        -   bicycloheteroaryl, and        -   bicycloheteroaryl substituted from 1 to 4 times by R^(b),            and    -   Y¹ is selected from:        -   C₁₋₆alkyl, and        -   C₁₋₆alkyl substituted with from: 1 to 9 substitutents            independently selected from:            -   fluoro,            -   chloro,            -   bromo,            -   iodo,            -   —OC₁₋₆alkyl,            -   —OC₁₋₆alkyl substituted with from 1 to 6 substituents                independently selected from: fluoro, oxo, —OH, —COOH,                —NH₂, and —CN,            -   mercapto,            -   —S(O)H,            -   —S(O)₂H,            -   oxo,            -   hydroxy,            -   amino,            -   —NHR^(x11),                -   where R^(x11) is selected from C₁₋₆alkyl, and                    C₁₋₆alkyl substituted with from 1 to 6 substituents                    independently selected from: fluoro, oxo, —OH,                    —COOH, —NH₂, —CN, —OC₁₋₅alkyl, —OC₁₋₅alkyl                    substituted from 1 to 6 times by fluoro and —NH₂,            -   NR^(x12)R^(x13),                -   where R^(x12) and R^(x13) are each independently                    selected from C₁₋₆alkyl, and C₁₋₆alkyl substituted                    with from 1 to 6 substituents independently selected                    from: fluoro, oxo, —OH, —COOH, —NH₂, and —CN,            -   —C(O)OH,            -   —C(O)NH₂,            -   aryl,            -   Oaryl,            -   heteroaryl,            -   Oheteroaryl,            -   —S(O)₂NH₂,            -   —NHS(O)₂H,            -   nitro, and            -   cyano, or    -   Y¹ is taken together with the adjacent —OH to form a        heterocyclic ring selected from:        -   morpholinyl,        -   morpholinyl substituted by —CH₃, and        -   oxazolidin-2-one;            each R^(a) is independently selected from:    -   fluoro,    -   chloro,    -   bromo,    -   iodo,    -   —OH,    -   C₁₋₆alkyl,    -   C₁₋₆alkyl substituted with from 1 to 5 substituents        independently selected from: fluoro, chloro, bromo, iodo,        C₁₋₄alkyloxy, —OH, C₁₋₄alkyl, phenyl, oxo, —COOH, —NO₂, —NH₂ and        —CN,    -   cyano,    -   —OC₁₋₆alkyl,    -   —OC₁₋₆alkyl substituted with from 1 to 5 substituents        independently selected from: fluoro, chloro, bromo, iodo,        C₁₋₄alkyloxy, —OH, C₁₋₄alkyl, phenyl, oxo, —COOH, —NO₂, —NH₂ and        —CN,    -   —Ophenyl,    -   —C(O)OC₁₋₆alkyl,    -   —C(O)OC₁₋₆alkyl substituted 1 to 5 times by fluoro, and    -   Ocycloalkyl; and        each R^(b) is independently selected from:    -   fluoro,    -   chloro,    -   bromo,    -   iodo,    -   —OH,    -   C₁₋₆alkyl,    -   C₁₋₆alkyl substituted with from 1 to 5 substituents        independently selected from: fluoro, chloro, bromo, iodo,        C₁₋₄alkyloxy, —OH, C₁₋₄alkyl, phenyl, oxo, —COOH, —NO₂, —NH₂ and        —CN,    -   cyano,    -   —OC₁₋₆alkyl,    -   —OC₁₋₆alkyl substituted with from 1 to 5 substituents        independently selected from: fluoro, chloro, bromo, iodo,        C₁₋₄alkyloxy, —OH, C₁₋₄alkyl, phenyl, oxo, —COOH, —NO₂, —NH₂ and        —CN,    -   Ocycloalkyl,    -   phenyl,    -   —C≡C—Si(CH₃)₃, and    -   —C≡C-cycloalkyl;        or a pharmaceutically acceptable salt thereof.        Suitably, in the compounds of Formula (I), R¹ is selected from:    -   aryl,    -   aryl substituted from 1 to 4 times by R^(a),    -   heteroaryl,    -   heteroaryl substituted from 1 to 4 times by R^(a),    -   bicycloheteroaryl, and    -   bicycloheteroaryl substituted from 1 to 4 times by R^(a).        Suitably, in the compounds of Formula (I), R² is selected from:    -   aryl,    -   aryl substituted from 1 to 4 times by R^(b),    -   heteroaryl,    -   heteroaryl substituted from 1 to 4 times by R^(b),    -   bicycloheteroaryl, and    -   bicycloheteroaryl substituted from 1 to 4 times by R^(b).        Suitably, in the compounds of Formula (I), Y¹ is selected from:    -   C₁₋₆alkyl, and    -   C₁₋₆alkyl substituted with from: 1 to 9 substitutents        independently selected from:        -   fluoro,        -   chloro,        -   bromo,        -   iodo,        -   —OC₁₋₆alkyl,        -   —OC₁₋₆alkyl substituted with from 1 to 6 substituents            independently selected from: fluoro, oxo, —OH, —COOH, —NH₂,            and —CN,        -   mercapto,        -   —S(O)H,        -   —S(O)₂H,        -   oxo,        -   hydroxy,        -   amino,        -   —NHR^(x11),            -   where R^(x11) is selected from C₁₋₆alkyl, and C₁₋₆alkyl                substituted with from 1 to 6 substituents independently                selected from: fluoro, oxo, —OH, —COOH, —NH₂, —CN,                —OC₁₋₅alkyl, —OC₁₋₅alkyl substituted from 1 to 6 times                by fluoro and —NH₂,        -   NR^(x12)R^(x13),            -   where R^(x12) and R^(x13) are each independently                selected from C₁₋₆alkyl, and C₁₋₆alkyl substituted with                from 1 to 6 substituents independently selected from:                fluoro, oxo, —OH, —COOH, —NH₂, and —CN,        -   —C(O)OH,        -   —C(O)NH₂,        -   aryl,        -   —Oaryl,        -   heteroaryl,        -   —Oheteroaryl,        -   —S(O)₂NH₂,        -   —NHS(O)₂H,        -   nitro, and        -   cyano, or    -   Y¹ is taken together with the adjacent —OH to form a        heterocyclic ring selected from:        -   morpholinyl,        -   morpholinyl substituted by —CH₃, and        -   oxazolidin-2-one.

Included in the compounds of Formula (I) are compounds of Formula (II):

wherein:

R²¹ is selected from:

-   -   aryl,    -   aryl substituted from 1 to 3 times by R^(a2)    -   heteroaryl,    -   heteroaryl substituted from 1 to 3 times by R^(a2)    -   bicycloheteroaryl, and    -   bicycloheteroaryl substituted from 1 to 3 times by R^(b2),

R²² is selected from:

-   -   aryl,    -   aryl substituted from 1 to 4 times by R^(b2),    -   heteroaryl, and    -   heteroaryl substituted from 1 to 3 times by R^(b2), and

Y²¹ is selected from:

-   -   C₁₋₆alkyl, and    -   C₁₋₆alkyl substituted with from: 1 to 9 substitutents        independently selected from:        -   fluoro,        -   chloro,        -   —OC₁₋₆alkyl,        -   —OC₁₋₆alkyl substituted with from 1 to 6 substituents            independently selected from: fluoro, oxo, —OH, —COOH, —NH₂,            and —CN,        -   oxo,        -   hydroxy,        -   amino,        -   —NHR^(x21),            -   where R^(x21) is selected from C₁₋₅alkyl, and C₁₋₅alkyl                substituted with from 1 to 6 substituents independently                selected from: fluoro, oxo, —OH, —COOH, —NH₂, and —CN,        -   —C(O)OH,        -   —C(O)NH₂,        -   nitro, and        -   cyano, or

Y²¹ is taken together with the adjacent —OH to form

-   -   morpholinyl, and    -   morpholinyl substituted by —CH₃;        each R^(a2) is independently selected from:    -   fluoro,    -   chloro,    -   bromo,    -   iodo,    -   —OH,    -   C₁₋₆alkyl,    -   C₁₋₆alkyl substituted with from 1 to 5 substituents        independently selected from: fluoro, chloro, bromo, iodo,        C₁₋₄alkyloxy, —OH, C₁₋₄alkyl, phenyl, oxo, —COOH, —NO₂, —NH₂ and        —CN,    -   cyano,    -   —OC₁₋₆alkyl,    -   —OC₁₋₆alkyl substituted with from 1 to 5 substituents        independently selected from: fluoro, chloro, bromo, iodo,        C₁₋₄alkyloxy, —OH, C₁₋₄alkyl, phenyl, oxo, —COOH, —NO₂, —NH₂ and        —CN,    -   —Ophenyl,    -   —C(O)OC₁₋₅alkyl,    -   —C(O)OC₁₋₅alkyl substituted 1 to 5 times by fluoro, and    -   —Ocycloalkyl; and

each R^(b2) is independently selected from:

-   -   fluoro,    -   chloro,    -   bromo,    -   —OH,    -   C₁₋₆alkyl,    -   C₁₋₆alkyl substituted with from 1 to 5 substituents        independently selected from: fluoro, chloro, bromo, iodo,        C₁₋₄alkyloxy, —OH, C₁₋₄alkyl, phenyl, oxo, —COOH, —NO₂, —NH₂ and        —CN,    -   cyano,    -   —OC₁₋₆alkyl,    -   —OC₁₋₆alkyl substituted with from 1 to 5 substituents        independently selected from: fluoro, chloro, bromo, iodo,        C₁₋₄alkyloxy, —OH, C₁₋₄alkyl, phenyl, oxo, —COOH, —NO₂, —NH₂ and        —CN,    -   —Ocycloalkyl, and    -   phenyl;        or a pharmaceutically acceptable salt thereof.        Suitably, in the compounds of Formula (II), R²¹ is selected        from:    -   aryl,    -   aryl substituted from 1 to 3 times by R^(a2),    -   heteroaryl,    -   heteroaryl substituted from 1 to 3 times by R^(a2),    -   bicycloheteroaryl, and    -   bicycloheteroaryl substituted from 1 to 3 times by R^(b2).        Suitably, in the compounds of Formula (II), R²² is selected        from:    -   aryl,    -   aryl substituted from 1 to 4 times by R^(b2),    -   heteroaryl, and    -   heteroaryl substituted from 1 to 3 times by R^(b2),        Suitably, in the compounds of Formula (II), Y²¹ is selected        from:    -   C₁₋₆alkyl, and    -   C₁₋₆alkyl substituted with from: 1 to 9 substitutents        independently selected from:        -   fluoro,        -   chloro,        -   —OC₁₋₆alkyl,        -   —OC₁₋₆alkyl substituted with from 1 to 6 substituents            independently selected from: fluoro, oxo, —OH, —COOH, —NH₂,            and —CN,        -   oxo,        -   hydroxy,        -   amino,        -   —NHR^(x21),            -   where R^(x21) is selected from C₁₋₅alkyl, and C₁₋₅alkyl                substituted with from 1 to 6 substituents independently                selected from: fluoro, oxo, —OH, —COOH, —NH₂, and —CN,        -   —C(O)OH,        -   —C(O)NH₂,        -   nitro, and        -   cyano, or    -   Y²¹ is taken together with the adjacent —OH to form        -   morpholinyl, and        -   morpholinyl substituted by —CH₃.

Included in the compounds of Formula (I) are compounds of Formula (III):

wherein:

R³¹ is selected from:

-   -   phenyl,    -   phenyl substituted from 1 to 3 times by R^(a3),    -   thiazole,    -   thiazole substituted from 1 to 3 times by R^(a3),    -   pyrimidine,    -   pyrimidine substituted from 1 to 3 times by R^(a3),    -   pyridine, and    -   pyridine substituted from 1 to 3 times by R^(a3);

R³² is selected from:

-   -   phenyl,    -   phenyl substituted from 1 to 3 times by R^(b3),    -   pyridine, and    -   pyridine substituted from 1 to 3 times by R^(b3); and

Y³¹ is selected from:

-   -   —CH₂OH,    -   —CH(OH)CH₃,    -   —CH(OH)CH₂CH₃,    -   —C(OH)(CH₃)₂,    -   —CH₂NH₂,    -   —CH₂NHR^(x30), and    -   —CH(NH₂)CH₃, or

Y³¹ is taken together with the adjacent —OH to form

-   -   morpholinyl,        -   where each R^(x30) is independently selected from:            C₁₋₆alkyl, and C₁₋₆alkyl substituted with from 1 to 6            substituents independently selected from: fluoro, oxo, —OH,            —COOH, —NH₂, and —CN;            each R^(a3) is independently selected from:    -   fluoro,    -   chloro,    -   bromo,    -   —OH,    -   C₁₋₆alkyl,    -   cyano,    -   —CF₃,    -   —C₁₋₅alkylCF₃,    -   —CHF₂,    -   —CH₂F,    -   —OC₁₋₅alkyl,    -   —OCF₃,    -   —O₁₋₅alkylCF₃,    -   —Ophenyl,    -   —Obenzyl,    -   —C₁₋₅alkylCN,    -   —C(O)OC₁₋₅alkyl,    -   —C(O)OH, and    -   —Ocycloalkyl; and        each R^(b3) is independently selected from:    -   fluoro,    -   chloro,    -   bromo,    -   —OH,    -   C₁₋₆alkyl,    -   cyano,    -   —CF₃,    -   —C₁₋₅alkylCF₃,    -   —CHF₂,    -   —CH₂F,    -   —OC₁₋₅alkyl,    -   —OCF₃,    -   —OC₁₋₅alkylCF₃,    -   —C(O)CH₃,    -   —OCHF₂,    -   —Ocyclopropyl, and    -   phenyl;    -   or a pharmaceutically acceptable salt thereof.        Suitably, in the compounds of Formula (III), R³¹ is selected        from:    -   phenyl,    -   phenyl substituted from 1 to 3 times by R^(a3),    -   thiazole,    -   thiazole substituted from 1 to 3 times by R^(a3),    -   pyrimidine,    -   pyrimidine substituted from 1 to 3 times by R^(a3),    -   pyridine, and    -   pyridine substituted from 1 to 3 times by R^(a3),        Suitably, in the compounds of Formula (III), R³² is selected        from:    -   phenyl,    -   phenyl substituted from 1 to 3 times by R^(b3),    -   pyridine, and    -   pyridine substituted from 1 to 3 times by R^(b3),        Suitably, in the compounds of Formula (III), Y³¹ is selected        from:    -   —CH₂OH,    -   —CH(OH)CH₃,    -   —CH(OH)CH₂CH₃,    -   —C(OH)(CH₃)₂,    -   —CH₂NH₂,    -   —CH₂NHR^(x30), and    -   —CH(NH₂)CH₃, or    -   Y³¹ is taken together with the adjacent —OH to form    -   morpholinyl,        -   where each R^(x30) is independently selected from:            C₁₋₆alkyl, and C₁₋₆alkyl substituted with from 1 to 6            substituents independently selected from: fluoro, oxo, —OH,            —COOH, —NH₂, and —CN.

Included in the compounds of Formula (I) are compounds of Formula (IV):

wherein:

R⁴¹ is selected from:

-   -   phenyl,    -   phenyl substituted from 1 to 3 times by R^(a4),    -   thiazole,    -   thiazole substituted from 1 to 3 times by R^(a3),    -   pyrimidine,    -   pyrimidine substituted from 1 to 3 times by R^(a3),    -   pyridine, and    -   pyridine substituted from 1 to 3 times by R^(a3);

R⁴² is selected from:

-   -   phenyl,    -   phenyl substituted from 1 to 3 times by R^(b4),    -   pyridine, and    -   pyridine substituted from 1 to 3 times by R^(b4); and

Y⁴¹ is selected from:

-   -   —CH₂OH,    -   —CH(OH)CH₃,    -   —CH₂NH₂, and    -   —CH₂NHR^(x40), or

Y³¹ is taken together with the adjacent —OH to form

-   -   morpholinyl,        -   where each R^(x40) is independently selected from:            C₁₋₆alkyl, and C₁₋₆alkyl substituted with from 1 to 6            substituents independently selected from: fluoro, oxo, —OH,            —COOH, —NH₂, and —CN;            each R^(a4) is independently selected from:    -   fluoro,    -   chloro,    -   bromo,    -   —OH,    -   C₁₋₆alkyl,    -   cyano,    -   —CF₃,    -   —C₁₋₅alkylCF₃,    -   —CHF₂,    -   —CH₂F,    -   —OCC₁₋₅alkyl,    -   —C(O)OC₁₋₅alkyl, and    -   —C(O)OH; and        each R^(b4) is independently selected from:    -   fluoro,    -   chloro,    -   bromo,    -   —OH,    -   C₁₋₆alkyl,    -   cyano,    -   —CF₃,    -   —C₁₋₅alkylCF₃,    -   —CHF₂,    -   —CH₂F,    -   —OC₁₋₅alkyl,    -   —OCF₃,    -   —OC₁₋₅alkylCF₃,    -   —C(O)CH₃,    -   —OCHF₂,    -   —Ocyclopropyl;        or a pharmaceutically acceptable salt thereof.        Suitably, in the compounds of Formula (IV), R⁴¹ is selected        from:    -   phenyl,    -   phenyl substituted from 1 to 3 times by R^(a4),    -   thiazole,    -   thiazole substituted from 1 to 3 times by R^(a3),    -   pyrimidine,    -   pyrimidine substituted from 1 to 3 times by R^(a3),    -   pyridine, and    -   pyridine substituted from 1 to 3 times by R^(a3),        Suitably, in the compounds of Formula (IV), R⁴² is selected        from:    -   phenyl,    -   phenyl substituted from 1 to 3 times by R^(b4),    -   pyridine, and    -   pyridine substituted from 1 to 3 times by R^(b4),        Suitably, in the compounds of Formula (IV), Y⁴¹ is selected        from:    -   —CH₂OH,    -   —CH(OH)CH₃,    -   —CH₂NH₂, and    -   —CH₂NHR^(x40), or    -   Y³¹ is taken together with the adjacent —OH to form        -   morpholinyl,            -   where each R^(x40) is independently selected from:                C₁₋₆alkyl, and C₁₋₆alkyl substituted with from 1 to 6                substituents independently selected from: fluoro, oxo,                —OH, —COOH, —NH₂, and —CN.

Suitably, in the compounds of Formula (I), R¹ is phenyl or pyridylindependently substituted from 1 to 3 times by cyano, bromo, chloroand/or fluoro.

Suitably, in the compounds of Formula (I), R² is a substituted phenyl.

Suitably, in the compounds of Formula (I), Y¹ is selected from: —CH₂OH,—CH(CH₃)OH and —CH₂NH₂.

Representative compounds of the invention include the specific compoundsdescribed herein, e.g., the compounds of Formula (I) of the Examples, aswell as any alternative stereoisomeric forms, free acid/base forms, saltforms, and alternative salt forms thereof (particularly pharmaceuticallyacceptable salt or alternative salt forms thereof), as applicable.Accordingly, in some embodiments the compound of the invention is acompound of Formula (I) selected from:

-   3-chloro-4-(((3R,4S)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;-   3-chloro-4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)    pyrrolidin-1-yl)sulfonyl)benzonitrile;-   4-(((3S,4S)-1-((2-chloro-4-cyanophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;-   4-(((3S,4S)-1-((2-chlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;-   4-(((3S,4S)-1-((2-chloro-4-fluorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;-   4-(((3S,4S)-1-((2-chloro-4-methylphenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;-   4-(((3S,4S)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;-   4-(((3S,4S)-1-((2-chloro-4-(trifluoromethoxy)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;-   4-(((3S,4S)-1-((2,4-dichloro-5-fluorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;-   4-(((3S,4R)-1-((2-chloro-4-cyanophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;-   4-(((3S,4R)-1-((2-chlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;-   4-(((3S,4R)-1-((2-chloro-4-fluorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;-   4-(((3S,4R)-1-((2-chloro-4-methylphenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;-   4-(((3S,4R)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;-   4-(((3S,4R)-1-((2-chloro-4-(trifluoromethoxy)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;-   4-(((3S,4R)-1-((2,4-dichloro-5-fluorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;-   5-chloro-2-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;-   (3R,4S)-4-((4-chlorophenyl)sulfonyl)-1-((2,4-dichlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;-   4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-(trifluoromethyl)benzonitrile;-   4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-methylbenzonitrile;-   4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-fluorobenzonitrile;-   4-(((3S,4R)-1-((2-bromo-4-fluorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   3-chloro-4-(((3S,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;-   4-(((3S,4S)-4-((4-bromophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile;-   4-(((3S,4R)-1-((4-chloro-2-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   3-chloro-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((6-(trifluoromethyl)pyridin-3-yl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;-   4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((6-(trifluoromethyl)pyridin-3-yl)sulfonyl)pyrrolidin-1-yl)sulfonyl)-3-(trifluoromethyl)benzonitrile;-   4-(((3S,4R)-4-hydroxy-4-(hydroxymethyl)-1-((2-methyl-4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   4-(((3S,4R)-1-((4-fluoro-2-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   4-(((3S,4R)-1-((4-bromo-2-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   4-(((3S,4R)-4-hydroxy-4-(hydroxymethyl)-1-((4-methoxy-2-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   4-(((3S,4R)-1-((2-bromo-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   4-(((3S,4R)-1-((2-bromophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   4-(((3S,4R)-1-((4-bromo-2-chlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-methoxybenzonitrile;-   4-(((3S,4R)-1-((2-fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   (3R,4S)-1-((2-chloro-4-(difluoromethyl)phenyl)sulfonyl)-4-((4-chlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;-   3-bromo-4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;-   3-bromo-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((6-(trifluoromethyl)pyridin-3-yl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;-   5-chloro-2-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((6-(trifluoromethyl)pyridin-3-yl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;-   4-(((3S,4R)-4-hydroxy-4-(hydroxymethyl)-1-((2-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   4-(((3S,4R)-1-((2-chloro-4-(difluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   (3R,4S)-1-((2-chloro-4-(fluoromethyl)phenyl)sulfonyl)-4-((4-chlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;-   4-(((3S,4R)-1-((2-chloro-4-(fluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   3-chloro-4-(((3R,4S)-4-((4-cyanophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;-   4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-ethylbenzonitrile;-   2-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;-   4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-(difluoromethyl)benzonitrile;-   4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-ethoxybenzonitrile;-   4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-cyclopropoxybenzonitrile;-   4-(((3S,4R)-1-((4-chloro-2-methoxyphenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   4-(((3S,4R)-1-((4-bromo-2-methoxyphenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   2-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;-   3-chloro-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;-   3-(difluoromethyl)-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;-   4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-1-yl)sulfonyl)-3-methoxybenzonitrile;-   3-cyclopropoxy-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;-   4-(((3S,4R)-1-((2-chloro-4-methylphenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   4-(((3S,4R)-1-((2-bromo-4-chlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   4-(((3S,4R)-1-((2-bromo-4-methoxyphenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   3-cyclopropoxy-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((5-(trifluoromethyl)pyridin-2-yl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;-   4-(((3S,4R)-1-((2-chloro-4-fluorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   4-(((3S,4R)-1-((2,4-dichloro-5-fluorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   methyl    4-(((3S,4R)-1-((4-chloro-2-(difluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzimidate;-   (3R,4S)-1-((4-chloro-2-(difluoromethyl)phenyl)sulfonyl)-4-((4-chlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;-   2-(5-chloro-2-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)phenyl)acetonitrile;-   (3R,4S)-4-((4-chlorophenyl)sulfonyl)-1-((2-(difluoromethoxy)pyridin-3-yl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;-   3-chloro-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-(thiazol-2-ylsulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;-   2-fluoro-4-(((3S,4R)-1-((2-fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   4-(((3S,4R)-1-((4-cyano-2-methylphenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile:-   2-fluoro-4-(((3S,4R)-4-hydroxy-4-(hydroxymethyl)-1-((2-methyl-4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   2-fluoro-4-(((3S,4R)-4-hydroxy-4-(hydroxymethyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   3-chloro-4-(((3R,4S)-4-((5-chlorothiazol-2-yl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;-   4-(((3R,4S)-4-((4-bromophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile;-   4-(((3S,4S)-1-((2,4-dichlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;-   (3S,4S)-4-((4-chloro-3-fluorophenyl)sulfonyl)-1-((2,4-dichlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;-   2-(((3S,4S)-4-((3,4-difluorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-5-(trifluoromethyl)benzonitrile;-   (3S,4S)-4-((4-chloro-3-fluorophenyl)sulfonyl)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;-   4-(((3S,4S)-1-((2,4-dichlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2,5-difluorobenzonitrile;-   2-chloro-4-(((3S,4S)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   4-(((3S,4S)-4-((5-bromopyridin-2-yl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile;-   4-(((3S,4R)-1-((2,4-dichlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   4-(((3S,4R)-1-((2,4-dichlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;-   5-chloro-2-(((3R,4S)-4-((4-cyanophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;-   (3R,4S)-1-((2,4-dichlorophenyl)sulfonyl)-4-((3,4-difluorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;-   4-(((3S,4R)-1-((2,4-dichlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-3-fluorobenzonitrile;-   4-(((3S,4R)-1-((2,4-dichlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2,6-difluorobenzonitrile;-   (3R,4S)-4-((4-chloro-3-fluorophenyl)sulfonyl)-1-((2,4-dichlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;-   4-(((3S,4R)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   4-(((3S,4S)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   4-(((3S,4R)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2,6-difluorobenzonitrile;-   5-(((3S,4R)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)picolinonitrile;-   2-(((3R,4S)-4-((3,4-difluorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-5-(trifluoromethyl)benzonitrile;-   2-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((3,4,5-trifluorophenyl)sulfonyl)pyrrolidin-1-yl)sulfonyl)-5-(trifluoromethyl)benzonitrile;-   4-(((3S,4R)-1-((2,4-dichlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2,5-difluorobenzonitrile;-   (3R,4S)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-3-(hydroxymethyl)-4-((4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-3-ol;-   (3R,4S)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-((4-chlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;-   (3R,4S)-4-((4-chloro-3-fluorophenyl)sulfonyl)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;-   (3R,4S)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-((6-chloropyridin-3-yl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;-   4-(((3S,4R)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-methylbenzonitrile;-   2-chloro-4-(((3S,4R)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   (3R,4S)-1-((2,4-dichlorophenyl)sulfonyl)-4-((4-fluorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;-   2-chloro-5-(((3S,4R)-1-((2,4-dichlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;-   3-chloro-4-(((3R,4S)-4-((4-ethylphenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;-   3-chloro-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((4-isopropylphenyl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;-   3-chloro-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((4-propylphenyl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;-   3-chloro-4-(((3R,4S)-4-((4-chloro-3-fluorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;-   (3R,4S)-1-((2,4-dichlorophenyl)sulfonyl)-3-(hydroxymethyl)-4-((2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)pyrrolidin-3-ol;-   3-chloro-4-(((3S,4S)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;-   3-chloro-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((5-(trifluoromethyl)pyridin-2-yl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;-   3-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)picolinonitrile;-   3-chloro-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;-   4-(((3R,4S)-4-((5-bromopyridin-2-yl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile;-   (3R,4S)-1-((2,4-dichlorophenyl)sulfonyl)-4-((3,4-dichlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;-   (3S,4S)-1-((2,4-dichlorophenyl)sulfonyl)-4-((3,4-dichlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;-   (3R,4S)-1-((2,4-dichlorophenyl)sulfonyl)-3-(hydroxymethyl)-4-((5-(trifluoromethyl)pyridin-2-yl)sulfonyl)pyrrolidin-3-ol;-   2-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-5-(trifluoromethyl)benzonitrile;-   (3R,4S)-1-((2,4-dichlorophenyl)sulfonyl)-3-(hydroxymethyl)-4-((6-(trifluoromethyl)pyridin-3-yl)sulfonyl)pyrrolidin-3-ol;-   3-chloro-4-(((3R,4S)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxy-3-((R)-1-hydroxyethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;-   3-chloro-4-(((3R,4S)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxy-3-((S)-1-hydroxyethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;-   4-(((3S,4S)-3-(aminomethyl)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile;-   4-(((3R,4S)-3-(aminomethyl)-4-((4-chlorophenyl)sulfonyl)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile;-   4-(((3S,4S)-3-(aminomethyl)-4-((4-chlorophenyl)sulfonyl)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile;-   3-chloro-4-(((3S,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-((methylamino)methyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;-   4-(((3R,4S)-3-(aminomethyl)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile;-   4-(((3S,4S)-3-(aminomethyl)-4-((4-chlorophenyl)sulfonyl)-3-hydroxypyrrolidin-1-yl)sulfonyl)benzonitrile;-   4-(((3R,4S)-3-(aminomethyl)-4-((4-chlorophenyl)sulfonyl)-3-hydroxypyrrolidin-1-yl)sulfonyl)benzonitrile;-   3-chloro-4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(((2,2,2-trifluoroethyl)amino)methyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;    and-   3-chloro-4-(((4S,5R)-4-((5-chloropyridin-2-yl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decan-2-yl)sulfonyl)benzonitrile;    or a pharmaceutically acceptable salt thereof.

The skilled artisan will appreciate that salts, includingpharmaceutically acceptable salts, of the compounds according to Formula(I) may be prepared. Indeed, in certain embodiments of the invention,salts including pharmaceutically-acceptable salts of the compoundsaccording to Formula (I) may be preferred over the respective free orunsalted compound. Accordingly, the invention is further directed tosalts, including pharmaceutically-acceptable salts, of the compoundsaccording to Formula (I).

The salts, including pharmaceutically acceptable salts, of the compoundsof the invention are readily prepared by those of skill in the art.

Typically, the salts of the present invention are pharmaceuticallyacceptable salts. Salts encompassed within the term “pharmaceuticallyacceptable salts” refer to non-toxic salts of the compounds of thisinvention.

Representative pharmaceutically acceptable acid addition salts include,but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate,ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate,bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate(camsylate), caprate (decanoate), caproate (hexanoate), caprylate(octanoate), cinnamate, citrate, cyclamate, digluconate,2,5-dihydroxybenzoate, disuccinate, dodecylsulfate (estolate), edetate(ethylenediaminetetraacetate), estolate (lauryl sulfate),ethane-1,2-disulfonate (edisylate), ethanesulfonate (esylate), formate,fumarate, galactarate (mucate), gentisate (2,5-dihydroxybenzoate),glucoheptonate (gluceptate), gluconate, glucuronate, glutamate,glutarate, glycerophosphorate, glycolate, hexylresorcinate, hippurate,hydrabamine (N,N′-di(dehydroabietyl)-ethylenediamine), hydrobromide,hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate,lactobionate, laurate, malate, maleate, malonate, mandelate,methanesulfonate (mesylate), methylsulfate, mucate,naphthalene-1,5-disulfonate (napadisylate), naphthalene-2-sulfonate(napsylate), nicotinate, nitrate, oleate, palmitate,p-aminobenzenesulfonate, p-aminosalicyclate, pamoate (embonate),pantothenate, pectinate, persulfate, phenylacetate,phenylethylbarbiturate, phosphate, polygalacturonate, propionate,p-toluenesulfonate (tosylate), pyroglutamate, pyruvate, salicylate,sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate,tartrate, teoclate (8-chlorotheophyllinate), thiocyanate, triethiodide,undecanoate, undecylenate, and valerate.

Representative pharmaceutically acceptable base addition salts include,but are not limited to, aluminium,2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS, tromethamine),arginine, benethamine (N-benzylphenethylamine), benzathine(N,N′-dibenzylethylenediamine), bis-(2-hydroxyethyl)amine, bismuth,calcium, chloroprocaine, choline, clemizole (1-pchlorobenzyl-2-pyrrolildine-1′-ylmethylbenzimidazole), cyclohexylamine,dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine,dimethylethanolamine, dopamine, ethanolamine, ethylenediamine,L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium,meglumine (N-methylglucamine), piperazine, piperidinyl, potassium,procaine, quinine, quinoline, sodium, strontium, t-butylamine, and zinc.

The compounds according to Formula I may contain one or more asymmetriccenters (also referred to as a chiral center) and may, therefore, existas individual enantiomers, diastereomers, or other stereoisomeric forms,or as mixtures thereof. Chiral centers, such as chiral carbon atoms, maybe present in a substituent such as an alkyl group. Where thestereochemistry of a chiral center present in a compound of Formula I,or in any chemical structure illustrated herein, if not specified thestructure is intended to encompass all individual stereoisomers and allmixtures thereof. Thus, compounds according to Formula I containing oneor more chiral centers may be used as racemic mixtures, enantiomericallyor diastereomerically enriched mixtures, or as enantiomerically ordiastereomerically pure individual stereoisomers.

The compounds according to Formula (I) and pharmaceutically acceptablesalts thereof may be in the form of isotopically-labelled compounds,wherein one or more atoms of Formula (I) are replaced by an atom havingan atomic mass or mass number different from the atomic mass or massnumber usually found in nature. Examples of such isotopes includeisotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur,fluorine, iodine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O,¹⁸, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I.

Isotopically-labelled compounds, for example those into whichradioactive isotopes such as ³H or ¹⁴C are incorporated, are useful indrug and/or substrate tissue distribution assays. Tritium, i.e., ³H, andcarbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their easeof preparation and detectability. ¹¹C and ¹⁸F isotopes are particularlyuseful in PET (positron emission tomography), and¹²⁵I isotopes areparticularly useful in SPECT (single photon emission computerizedtomography), both are useful in brain imaging. Further, substitutionwith heavier isotopes such as deuterium, i.e., ²H, can afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements and,hence, may be preferred in some circumstances. Isotopically labelledcompounds can generally be prepared by substituting a readily availableisotopically labelled reagent for a non-isotopically labelled reagent.

The compounds according to Formula (I) may also contain double bonds orother centers of geometric asymmetry. Where the stereochemistry of acenter of geometric asymmetry present in Formula (I), or in any chemicalstructure illustrated herein, is not specified, the structure isintended to encompass the trans (E) geometric isomer, the cis (Z)geometric isomer, and all mixtures thereof. Likewise, all tautomericforms are also included in Formula (I) whether such tautomers exist inequilibrium or predominately in one form.

The compounds of the invention may exist in solid or liquid form. Insolid form, compound of the invention may exist in a continuum of solidstates ranging from fully amorphous to fully crystalline. The term‘amorphous’ refers to a state in which the material lacks long rangeorder at the molecular level and, depending upon the temperature, mayexhibit the physical properties of a solid or a liquid. Typically suchmaterials do not give distinctive X-ray diffraction patterns and, whileexhibiting the properties of a solid, are more formally described as aliquid. Upon heating, a change from solid to liquid properties occurswhich is characterized by a change of state, typically second order(‘glass transition’). The term ‘crystalline’ refers to a solid phase inwhich the material has a regular ordered internal structure at themolecular level and gives a distinctive X-ray diffraction pattern withdefined peaks. Such materials when heated sufficiently will also exhibitthe properties of a liquid, but the change from solid to liquid ischaracterized by a phase change, typically first order (‘meltingpoint’).

The compounds of the invention may have the ability to crystallize inmore than one form, a characteristic, which is known as polymorphism(“polymorphs”). Polymorphism generally can occur as a response tochanges in temperature or pressure or both and can also result fromvariations in the crystallization process. Polymorphs can bedistinguished by various physical characteristics known in the art suchas x-ray diffraction patterns, solubility and melting point.

The compounds of Formula (I) may exist in solvated and unsolvated forms.As used herein, the term “solvate” refers to a complex of variablestoichiometry formed by a solute (in this invention, a compound ofFormula (I) or a salt) and a solvent. Such solvents, for the purpose ofthe invention, may not interfere with the biological activity of thesolute. The skilled artisan will appreciate that pharmaceuticallyacceptable solvates may be formed for crystalline compounds whereinsolvent molecules are incorporated into the crystalline lattice duringcrystallization. The incorporated solvent molecules may be watermolecules or non-aqueous such as ethanol, isopropanol, DMSO, aceticacid, ethanolamine, and ethyl acetate molecules. Crystalline latticestructures incorporated with water molecules are typically referred toas “hydrates”. Hydrates include stoichiometric hydrates as well ascompositions containing variable amounts of water.

It is also noted that the compounds of Formula (I) may form tautomers.‘Tautomers’ refer to compounds that are interchangeable forms of aparticular compound structure, and that vary in the displacement ofhydrogen atoms and electrons. Thus, two structures may be in equilibriumthrough the movement of rr electrons and an atom (usually H). Forexample, enols and ketones are tautomers because they are rapidlyinterconverted by treatment with either acid or base. It is understoodthat all tautomers and mixtures of tautomers of the compounds of thepresent invention are included within the scope of the compounds of thepresent invention.

While aspects for each variable have generally been listed aboveseparately for each variable this invention includes those compounds inwhich several or each aspect in Formula (I) is selected from each of theaspects listed above. Therefore, this invention is intended to includeall combinations of aspects for each variable.

Definitions

“Alkyl” refers to a hydrocarbon chain having the specified number of“member atoms”. For example, C₁-C₆ alkyl refers to an alkyl group havingfrom 1 to 6 member atoms. Alkyl groups may be saturated, unsaturated,straight or branched. Representative branched alkyl groups have one,two, or three branches. Alkyl includes but is not limited to: methyl,ethyl, ethylene, ethynyl, propyl (n-propyl and isopropyl), butene, butyl(n-butyl, isobutyl, and t-butyl), pentyl and hexyl.

“Alkoxy” refers to an —O-alkyl group wherein “alkyl” is as definedherein. For example, C₁-C₄alkoxy refers to an alkoxy group having from 1to 4 carbon member atoms. Examples of such groups include but is notlimited to: methoxy, ethoxy, propoxy, isopropoxy, butoxy, and t-butoxy.

“Aryl” refers to an aromatic hydrocarbon ring system. Aryl groups aremonocyclic, bicyclic, and tricyclic ring systems having a total of fiveto fourteen ring member atoms, wherein at least one ring system isaromatic and wherein each ring in the system contains 3 to 7 memberatoms, such as but no limited to: phenyl, dihydroindene, naphthalene,tetrahydronaphthalene and biphenyl. Suitably aryl is phenyl.

“Cycloalkyl”, unless otherwise defined, refers to a saturated orunsaturated non aromatic hydrocarbon ring having from three to sevencarbon atoms. Cycloalkyl groups are monocyclic ring systems. Forexample, C₃-C₇ cycloalkyl refers to a cycloalkyl group having from 3 to7 member atoms. Examples of cycloalkyl as used herein include but is notlimited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptyl. Suitablycycloalkyl is selected from: cyclopropyl, cyclopentyl and cyclohexyl.

“Heteroaryl” refers to a monocyclic aromatic 4 to 8 member ringcontaining from 1 to 7 carbon atoms and containing from 1 to 4heteroatoms, provided that when the number of carbon atoms is 3, thearomatic ring contains at least two heteroatoms. Heteroaryl groupscontaining more than one heteroatom may contain different heteroatoms.Heteroaryl includes: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, furanyl, furazanyl, thienyl,triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,tetrazinyl. Suitably, “heteroaryl” includes: pyrazole, pyrrole,isoxazole, pyridine, pyrimidine, pyridazine, and imidazole.

“Bicycloheteroaryl” refers to two fused rings, at least one of which isaromatic, containing from 1 to 6 heteroatoms as member atoms.Bicycloheteroaryl groups containing more than one heteroatom may containdifferent heteroatoms. Bicycloheteroaryl rings have from 6 to 11 memberatoms. Bicycloheteroaryl includes: 1H-pyrrolo[3,2-c]pyridine,1H-pyrazolo[4,3-c]pyridine, 1H-pyrazolo[3,4-d]pyrimidine,1H-pyrrolo[2,3-d]pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine,thieno[3,2-c]pyridine, thieno[2,3-d]pyrimidine, furo[2,3-c]pyridine,furo[2,3-d]pyrimidine, indolyl, isoindolyl, indolizinyl, indazolyl,purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl,pteridinyl, cinnolinyl, azabenzimidazolyl, tetrahydrobenzimidazolyl,benzoxadiazole, imidazothiazole, benzimidazolyl, benopyranyl,benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl,benzothienyl, imidazo[4.5-c]pyridine, imidazo[4.5-b]pyridine,furopyridinyl and napthyridinyl. Suitably “Bicycloheteroaryl” includes:benzoxadiazole and imidazothiazole.

“Heteroatom” refers to a nitrogen, sulphur or oxygen atom.

“Halogen” and “halo” refers to a fluorine, chlorine, bromine, or iodineatom.

As used herein, the term “mercapto” refers to the group —SH.

As used herein, the term “oxo” refers to the group ═O.

As used herein, the term “hydroxy” refers to the group —OH.

As used herein, the term “amino” refers to the group —NH₂.

As used herein, the term “carboxy” refers to the group —C(O)OH.

As used herein, the term “cyano” refers to the group —CN.

As used herein, the term “nitro” refers to the group —NO₂.

Compound Preparation

The compounds according to Formula (I) are prepared using conventionalorganic synthetic methods. Suitable synthetic routes are depicted belowin the following general reaction schemes. All of the starting materialsare commercially available or are readily prepared from commerciallyavailable starting materials by those of skill in the art.

The skilled artisan will appreciate that if a substituent describedherein is not compatible with the synthetic methods described herein,the substituent may be protected with a suitable protecting group thatis stable to the reaction conditions. The protecting group may beremoved at a suitable point in the reaction sequence to provide adesired intermediate or target compound. Suitable protecting groups andthe methods for protecting and de-protecting different substituentsusing such suitable protecting groups are well known to those skilled inthe art; examples of which may be found in T. Greene and P. Wuts,Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY(1999). In some instances, a substituent may be specifically selected tobe reactive under the reaction conditions used. Under thesecircumstances, the reaction conditions convert the selected substituentinto another substituent that is either useful as an intermediatecompound or is a desired substituent in a target compound.

As used in the Schemes, “Ar” groups represent corresponding groups onany of Formulas I to IV. The compounds of Formulas I to IV can beprepared generally as described in the Schemes using appropriatesubstitutions for starting materials.

As shown in Scheme 1, the compounds of Formula (I) can be prepared by amulti-step sequence. The mesylate of the Boc-protected pyrrolidine canundergo displacement with an appropriately substituted thiophenol in theprescence of a base such as K₂CO₃ to give the corresponding sulfide. Thesulfide can be oxidized to the sulfone by treatment with m-CPBA. Theexocyclic olefin of the pyrrolidine ring can be dihydroxylated withcatalytic OSO₄ using NMO as a cooxidant and the trans-diastereomer canbe obtained by separation techniques such as silica gel columnchromatography either in this step or in subsequent steps. Removal ofthe Boc protecting group with an acid such as TFA followed by treatmentof the deprotected pyrrolidine with an appropriately substitutedarylsulfonyl chloride and base such as NaHCO₃ provides compounds ofFormula (I).

Alternatively, compounds of Formula (I) can be prepared as shown inScheme 2. The mesylate of the Boc protected pyrrolidine can undergodisplacement with an appropriately substituted thiophenol and base suchas K₂CO₃ to give the corresponding sulfide. The exocyclic olefin of thepyrrolidine ring can be dihydroxylated with catalytic OsO₄ using NMO asa cooxidant, and the mixture of cis/trans diasteromer intermediates iscarried through the subsequent reactions. Oxidation of the sulfide tothe sulfone can be accomplished by m-CPBA. Removal of the Boc protectinggroup with an acid such as HCl in dioxane, followed by treatment of thedeprotected pyrrolidine with an appropriately substituted arylsulfonylchloride and base such as NaHCO₃ provides compounds of Formula (I) as amixture of cis/trans diastereomers. Enantiopure trans and cis isomerscan be obtained by separation techniques such as silica gel columnchromatography to give the individual diasteroemeric cis and transcompounds of Formula (I).

Alternatively, compounds of Formula (I) can be prepared as shown inScheme 3. The mesylate of the Boc protected pyrrolidine can undergodisplacement with an appropriately substituted thiophenol and base suchas K₂CO₃ to give the corresponding sulfide. The exocyclic olefin of thepyrrolidine ring can be dihydroxylated with catalytic OsO₄ using NMO asa cooxidant, and the mixture of cis/trans diasteromers produced can becarried through the next two steps. Oxidation of the sulfide to thesulfone can be accomplished by m-CPBA. Protection of the dihydroxycompound as the cyclic ketal can be accomplished with2,2-dimethoxypropane and tosic acid in water and the individualenantiopure cis and trans diastereomers can be obtained by separationtechniques such as silica gel column chromatography. Either the cis ortrans diastereomer can be carried through the next two steps to providecompounds of Formula (I). The Boc and cyclic ketal protecting groups canbe hydrolyzed to the unprotected pyrrolidine with an acid such as TFA.Treatment of the deprotected pyrrolidine with an appropriatelysubstituted arylsulfonyl chloride and base such as NaHCO₃ providecompounds of Formula (I).

Alternatively, compounds of Formula (I) can be prepared as shown inScheme 4. The Boc group of the protected hydroxypyrrolidine can beremoved with an acid such as TFA and the unprotected pyrrolidine can betreated with an appropriately substituted arylsulfonyl chloride to givethe sulfonamide. Mesylation of the hydroxyl group with mesyl chloridefollowed by displacement with an appropriately substituted thiophenoland base such as K₂CO₃ can provide the sulfide. The exocyclic olefin ofthe pyrrolidine ring can be dihydroxylated with catalytic OsO₄ using NMOas a cooxidant, and the individual enantiopure trans and cis isomers canbe obtained by separation techniques such as silica gel columnchromatography. Either the cis or trans diastereomer can be oxidizedwith m-CPBA to give compounds of Formula (I).

As shown in Scheme 5, compounds of Formula (I) can be prepared by amulti-step sequence from substituted sulfonyl chlorides. The appropriatesulfonyl chloride can be substituted with an alkyl amine using a basesuch as K₂CO₃ to give a secondary sulfonamide which can then be treatedwith an alkyl halide to give the tertiary sulfonamide. The tertiarysulfonamide can be cyclized by olefin metathesis using a catalyst, suchas Grubbs Catalyst, 2^(nd) Generation, to give the pyrroline. Thepyrroline can be epoxidized with m-CPBA and the epoxide ring opened withan appropriately substituted thiophenol using a base such as Cs₂CO₃ togive the pyrrolidine as a racemic mixture of trans diastereomers. Thesulfide can be oxidized to the sulfone with m-CPBA and the racemic cisand trans diastereomers can separated by techniques such as silica gelcolumn chromatography. The silyl protecting group of the individualdiastereomers can be removed with TBAF in acetic acid and the individualenantiomers separated by techniques such as chiral chromatography togive compounds of Formula (I).

As shown in Scheme 6, the compounds of Formula (I) can be prepared by amulti-step sequence. Mesylation of the hydroxyl group of the Bocprotected pyrrolidine with mesyl chloride followed by displacement withan appropriately substituted thiophenol with a base such as K₂CO₃provide the sulfide. The exocyclic olefin of the pyrrolidine ring can bedihydroxylated with catalytic OsO₄ using NMO as a cooxidant, and themixture of cis/trans diasteromers produced can be carried into the nextstep. Protection of the dihydroxy compound as the cyclic ketal can beaccomplished with 2,2-dimethoxypropane and tosic acid in water and themixture of cis/trans diastereomers can be separated by techniques suchas silica gel column chromatography. Either the individual cis or transdiastereomer can be carried through the following steps to providecompounds of Formula (I). The Boc and cyclic ketal protecting groups canbe hydrolyzed with an acid such as TFA and the deprotected pyrrolidinetreated with an appropriately substituted arylsulfonyl chloride and basesuch as NaHCO₃ to give the sulfonamide. The pyrrolidine hydroxyl groupcan be mesylated with mesyl chloride, the mesylate displaced with sodiumazide and the azide reduced to the amine with polymer supportedtriphenylphosphine. Protection of the amine with Boc anyhydride,oxidation of the sulfide to sulfone with m-CPBA and removal of the Bocprotecting group with TFA provide compounds of Formula (I).

Alternatively, compounds of Formula (I) can be prepared by a multi-stepsequence as shown in scheme 7. Mesylation of the hydroxyl group of theBoc protected pyrrolidine with mesyl chloride followed by displacementwith an appropriately substituted thiophenol gives the correspondingsulfide. The exocyclic olefin of the pyrrolidine ring can bedihydroxylated with catalytic OsO₄ using NMO as a cooxidant, and themixture of cis/trans diasteromers produced can be carried throughsubsequent steps until separated. The pyrrolidine hydroxyl group can bemesylated with mesyl chloride, the mesylate displaced with sodium azideand the azide reduced to the amine with trimethylphosphine. Conversionto the morpholin-3-one can be carried out by acylation of the amine with2-chloroacetyl chloride and TEA followed by cyclization with t-BuOK.Removal of the Boc protecting group with an acid such as TFA, andtreatment with an appropriately substituted arylsulfonyl chlorideprovide the sulfonamide. Oxidation of the sulfide with m-CPBA providethe sulfone as a mixture of cis/trans diastereomers which can now beseparated to individual enantiomers by techniques such as silica gelcolumn chromatography. Either the individual cis or trans diastereomercan be carried through the following steps to give compounds of Formula(I). The morpholin-3-one can be converted to the morpholine by reductionwith Borane in THF, and the amine is Boc protected using Boc anhydrideto simplify purification by techniques such as silica gel columnchromatography. The Boc protecting group can be removed by acid such asHCl to give compounds of Formula (I).

Biological Activity

As stated above, the compounds according to Formula I are TRPV4antagonists. The biological activity of the compounds according toFormula I can be determined using any suitable assay for determining theactivity of a candidate compound as a TRPV4 antagonist, as well astissue and in vivo models. The biological activity of the compounds ofFormula (I) are demonstrated by the following tests.

FLIPR Assay for hTRPV4 Expressed in BHK Cells:

TRPV4 channel activation results in an influx of divalent and monovalentcations including calcium. The resulting changes in intracellularcalcium were monitored using a calcium specific fluorescent dye Fluo-4(MDS Analytical Technologies). BHK/AC9 cells transduced with BacMamvirus expressing the human TRPV4 gene at a MOI of 78 were plated in a384 well poly-D lysine coated plate (15,000 cells/well in 50 μL culturemedium containing DMEM/F12 with 15 mM HEPES, 10% FBS, 1%Penicillin-Streptomycin and 1% L-glutamine). Cells were incubated for 24hours at 37° C. and 5% CO₂. Culture medium was then aspirated using aTecan plate-washer and replaced with 20 μL/well of dye loading buffer:HBSS, 500 μM Brilliant Black (MDS Analytical Technologies), and 2 μMFluo-4 AM. Dye loaded plates were then incubated in the dark at roomtemperature for 1˜1.5 hours. 10 μL of test compounds diluted in HBSS(with 1.5 mM Calcium Chloride, 1.5 mM Magnesium Chloride and 10 mMHEPES, pH 7.4)+0.01% Chaps was added to each individual well of theplate, incubated for 10 min at room temperature in the dark and then 10μL of agonist(N—((S)-1-(((R)-1-((2-cyanophenyl)sulfonyl)-3-oxoazepan-4-yl)amino)-4-methyl-1-oxopentan-2-yl)benzo[b]thiophene-2-carboxamide,(Thorneloe et al, Sci. Transl. Med. (2012), 4, 159ra148) (hereinafter:Agonist Compound) was added to have a final concentration equals to theagonist EC80. Calcium signals were measured using FLIPRTETRA (MDSAnalytical Technologies) or FLIPR384 (MDS Analytical Technologies) andthe inhibition of Agonist Compound-induced calcium signal by the testcompound was determined.

All examples described herein possessed TRPV4 biological activity withIC₅₀ ranges from 0.1 nM-1 μM (see table below).

The compound of Example 1 was tested generally according to the aboveTRPV4 assay and in at least one set of experimental runs exhibited anaverage IC₅₀ (nM) value of 5.

The compound of Example 22 was tested generally according to the aboveTRPV4 assay and in at least one set of experimental runs exhibited anaverage IC₅₀ (nM) value of 13.

EX # IC₅₀ 1 +++ 2 +++ 3 +++ 4 ++ 5 ++ 6 ++ 7 ++ 8 ++ 9 ++ 10 +++ 11 ++12 +++ 13 +++ 14 +++ 15 ++ 16 +++ 17 +++ 18 ++ 19 +++ 20 ++ 21 ++ 22 ++23 ++ 24 ++ 25 +++ 26 ++ 27 ++ 28 ++ 29 +++ 30 +++ 31 ++ 32 ++ 33 ++ 34+++ 35 +++ 36 ++ 37 ++ 38 +++ 39 ++ 40 ++ 41 ++ 42 ++ 43 ++ 44 ++ 45 +++46 ++ 47 ++ 48 +++ 49 ++ 50 ++ 51 ++ 52 ++ 53 ++ 54 +++ 55 +++ 56 ++ 57++ 58 ++ 59 +++ 60 ++ 61 ++ 62 ++ 63 ++ 64 ++ 65 ++ 66 ++ 67 ++ 68 ++ 69++ 70 +++ 71 ++ 72 ++ 73 ++ 74 +++ 75 +++ 76 ++ 77 ++ 78 ++ 79 ++ 80 ++81 ++ 82 +++ 83 +++ 84 +++ 85 ++ 86 ++ 87 +++ 88 +++ 89 ++ 90 ++ 91 ++92 ++ 93 ++ 94 ++ 95 ++ 96 ++ 97 ++ 98 ++ 99 ++ 100 ++ 101 ++ 102 ++ 103++ 104 ++ 105 ++ 106 ++ 107 +++ 108 ++ 109 ++ 110 ++ 111 ++ 112 ++ 113+++ 114 ++ 115 ++ 116 ++ 117 +++ 118 ++ 119 +++ 120 +++ 121 +++ 122 +++123 +++ 124 +++ 125 +++ 126 ++ 127 ++ 128 ++ 129 ++ IC₅₀ Ranges: 0.1-10nM (+++), >10-100 nM (++), >100-1000 nM (+).

Methods of Use

In yet another aspect, this invention provides a compound of Formula (I)or a pharmaceutically acceptable salt thereof in the treatment of adisease state selected from: atherosclerosis, disorders related tovasogenic edema, postsurgical abdominal edema, ocular edema, cerebraledema, local and systemic edema, fluid retention, sepsis, hypertension,inflammation, bone related dysfunctions and congestive heart failure,pulmonary disorders, chronic obstructive pulmonary disorder, ventilatorinduced lung injury, high altitude induced pulmonary edema, acuterespiratory distress syndrome, acute lung injury, pulmonary fibrosis andother fibrosis-related disorders, sinusitis/rhinitis, asthma, COPD,cough; including acute cough, sub-acute cough and chronic cough,pulmonary hypertension, overactive bladder, cystitis, pain, motor neurondisorders, genetic gain of function disorders, amyotrophic lateralsclerosis, multiple sclerosis, cardiovascular disease, acute, chronicand polycystic kidney disease, stroke, hydrocephalus, glaucoma,retinopathy, endometriosis, pre-term labor, dermatitis, renaldysfunction, pruritus, pruritus in liver disease, ascites andcomplications of portal hypertension and liver cirrhosis, diabetes,metabolic disorder, obesity, migraine, Alzheimer's disease,pancreatitis, tumor suppression, immunosuppression, osteoarthritis,crohn's disease, colitis, diarrhea, intestinal irregularity(hyperreactivity/hyporeactivity), fecal incontinence, irritable bowelsyndrome (IBS), constipation, intestinal pain and cramping, celiacdisease, lactose intolerance, and flatulence, through the administrationof a compound of Formula (I) or a pharmaceutically acceptable saltthereof. Suitably the compounds of the invention are used in thetreatment of congestive heart failure. Suitably the compounds of theinvention are used in the treatment of acute lung injury. Suitably thecompounds of the invention are used in the treatment of cerebral edema.Suitably the compounds of the invention are used in the treatment ofheart failure. Suitably the compounds of the invention are used in thetreatment of cough; including acute cough, sub-acute cough and chroniccough. Suitably the compounds of the invention are used in the treatmentof acute respiratory distress syndrome. Accordingly, in another aspectthe invention is directed to methods of treating such conditions.

The compounds of Formula (I) are tested for their ability to treat coughin in vivo in pre-clinical models in which cough is induced, for examplethe guinea pig model cited in Bonvini S J, et al., J Allergy ClinImmunol. 2016 July; 138(1):249-261.e12. The efficacy of compounds ofFormula (I) are tested for their ability to treat cough; including acutecough, sub-acute cough and chronic cough, in people using the objectivecough monitoring and specific quality of life instruments as cited inAbdulqawi R, et al. Lancet. 2015 Mar. 28; 385(9974):1198-1205.

The methods of treatment of the invention comprise administering a safeand effective amount of a compound according to Formula I or apharmaceutically-acceptable salt thereof to a patient in need thereof.

As used herein, “treat” in reference to a condition means: (1) toameliorate the condition or one or more of the biological manifestationsof the condition, (2) to interfere with (a) one or more points in thebiological cascade that leads to or is responsible for the condition or(b) one or more of the biological manifestations of the condition, (3)to alleviate one or more of the symptoms or effects associated with thecondition, or (4) to slow the progression of the condition or one ormore of the biological manifestations of the condition.

The term “treating” and derivatives thereof refers to therapeutictherapy. Therapeutic therapy is appropriate to alleviate symptoms or totreat at early signs of disease or its progression.

The skilled artisan will appreciate that “prevention” is not an absoluteterm. In medicine, “prevention” is understood to refer to theprophylactic administration of a drug to substantially diminish thelikelihood or severity of a condition or biological manifestationthereof, or to delay the onset of such condition or biologicalmanifestation thereof.

As used herein, “safe and effective amount” in reference to a compoundof the invention or other pharmaceutically-active agent means an amountof the compound sufficient to treat the patient's condition but lowenough to avoid serious side effects (at a reasonable benefit/riskratio) within the scope of sound medical judgment. A safe and effectiveamount of a compound will vary with the particular compound chosen (e.g.consider the potency, efficacy, and half-life of the compound); theroute of administration chosen; the condition being treated; theseverity of the condition being treated; the age, size, weight, andphysical condition of the patient being treated; the medical history ofthe patient to be treated; the duration of the treatment; the nature ofconcurrent therapy; the desired therapeutic effect; and like factors,but can nevertheless be routinely determined by the skilled artisan.

As used herein, “patient” or “subject” refers to a human or othermammal.

In a further aspect, the invention provides for a compound of Formula(I) or a pharmaceutically acceptable salt thereof for use in thetreatment of atherosclerosis, disorders related to vasogenic edema,postsurgical abdominal edema, ocular edema, cerebral edema, local andsystemic edema, fluid retention, sepsis, hypertension, inflammation,bone related dysfunctions and congestive heart failure, pulmonarydisorders, chronic obstructive pulmonary disorder, ventilator inducedlung injury, high altitude induced pulmonary edema, acute respiratorydistress syndrome, acute lung injury, pulmonary fibrosis and otherfibrosis-related disorders, sinusitis/rhinitis, asthma, COPD, cough;including acute cough, sub-acute cough and chronic cough, pulmonaryhypertension, overactive bladder, cystitis, pain, motor neurondisorders, genetic gain of function disorders, amyotrophic lateralsclerosis, multiple sclerosis, cardiovascular disease, acute, chronicand polycystic kidney disease, stroke, hydrocephalus, glaucoma,retinopathy, endometriosis, pre-term labor, dermatitis, pruritus,pruritus in liver disease, ascites and complications of portalhypertension and liver cirrhosis, diabetes, metabolic disorder, obesity,migraine, Alzheimer's disease, pancreatitis, tumor suppression,immunosuppression, osteoarthritis, crohn's disease, renal dysfunction,colitis, diarrhea, intestinal irregularity(hyperreactivity/hyporeactivity), fecal incontinence, irritable bowelsyndrome (IBS), constipation, intestinal pain and cramping, celiacdisease, lactose intolerance, or flatulence. Suitably the inventionprovides for a compound of Formula (I) or a pharmaceutically acceptablesalt thereof for use in the treatment of congestive heart failure.Suitably the invention provides for a compound of Formula (I) or apharmaceutically acceptable salt thereof for use in the treatment ofacute lung injury. Suitably the invention provides for a compound ofFormula (I) or a pharmaceutically acceptable salt thereof for use in thetreatment cerebral edema. Suitably the invention provides for a compoundof Formula (I) or a pharmaceutically acceptable salt thereof for use inthe treatment of heart failure. Suitably the invention provides for acompound of Formula (I) or a pharmaceutically acceptable salt thereoffor use in the treatment of cough; including acute cough, sub-acutecough and chronic cough. Suitably the invention provides for a compoundof Formula (I) or a pharmaceutically acceptable salt thereof for use inthe treatment of acute respiratory distress syndrome.

In another aspect, the invention provides for the use of a compound ofFormula (I) or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for the treatment of atherosclerosis,disorders related to vasogenic edema, postsurgical abdominal edema,ocular edema, cerebral edema, local and systemic edema, fluid retention,sepsis, hypertension, inflammation, bone related dysfunctions andcongestive heart failure, pulmonary disorders, chronic obstructivepulmonary disorder, ventilator induced lung injury, high altitudeinduced pulmonary edema, acute respiratory distress syndrome, acute lunginjury, pulmonary fibrosis and other fibrosis-related disorders,sinusitis/rhinitis, asthma, COPD, cough; including acute cough,sub-acute cough and chronic cough, pulmonary hypertension, overactivebladder, cystitis, pain, motor neuron disorders, genetic gain offunction disorders, amyotrophic lateral sclerosis, multiple sclerosis,cardiovascular disease, acute, chronic and polycystic kidney disease,stroke, hydrocephalus, glaucoma, retinopathy, endometriosis, pre-termlabor, dermatitis, pruritus, pruritus in liver disease, ascites andcomplications of portal hypertension and liver cirrhosis, diabetes,metabolic disorder, obesity, migraine, Alzheimer's disease,pancreatitis, tumor suppression, immunosuppression, osteoarthritis,crohn's disease, colitis, diarrhea, intestinal irregularity(hyperreactivity/hyporeactivity), fecal incontinence, irritable bowelsyndrome (IBS), constipation, intestinal pain and cramping, celiacdisease, lactose intolerance, or flatulence. Suitably the inventionprovides for the use of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof in the manufacture of a medicament for thetreatment of congestive heart failure. Suitably the invention providesfor the use of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof in the manufacture of a medicament for thetreatment of acute lung injury. Suitably the invention provides for theuse of a compound of Formula (I) or a pharmaceutically acceptable saltthereof in the manufacture of a medicament for the treatment of cerebraledema. Suitably the invention provides for a compound of Formula (I) ora pharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of heart failure. Suitably the inventionprovides for a compound of Formula (I) or a pharmaceutically acceptablesalt thereof in the manufacture of a medicament for the treatment ofcough; including acute cough, sub-acute cough and chronic cough.Suitably the invention provides for a compound of Formula (I) or apharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of acute respiratory distress syndrome.

The compounds of the invention may be administered by any suitable routeof administration, including both systemic administration and topicaladministration. Systemic administration includes oral administration,parenteral administration, transdermal administration, rectaladministration, and administration by inhalation. Parenteraladministration refers to routes of administration other than enteral,transdermal, or by inhalation, and is typically by injection orinfusion. Parenteral administration includes intravenous, intramuscular,and subcutaneous injection or infusion. Inhalation refers toadministration into the patient's lungs whether inhaled through themouth or through the nasal passages. Topical administration includesapplication to the skin as well as intraocular, otic, intravaginal, andintranasal administration. Suitably the administration is oral. Suitablythe administration is intravenous. Suitably the administration is byinhalation.

The compounds of the invention may be administered once or according toa dosing regimen wherein a number of doses are administered at varyingintervals of time for a given period of time. For example, doses may beadministered one, two, three, or four times per day. Doses may beadministered until the desired therapeutic effect is achieved orindefinitely to maintain the desired therapeutic effect. Suitable dosingregimens for a compound of the invention depend on the pharmacokineticproperties of that compound, such as absorption, distribution, andhalf-life, which can be determined by the skilled artisan. In addition,suitable dosing regimens, including the duration such regimens areadministered, for a compound of the invention depend on the conditionbeing treated, the severity of the condition being treated, the age andphysical condition of the patient being treated, the medical history ofthe patient to be treated, the nature of concurrent therapy, the desiredtherapeutic effect, and like factors within the knowledge and expertiseof the skilled artisan. It will be further understood by such skilledartisans that suitable dosing regimens may require adjustment given anindividual patient's response to the dosing regimen or over time asindividual patient needs change.

Typical daily dosages may vary depending upon the particular route ofadministration chosen. Typical dosages for oral administration rangefrom 1 mg to 1000 mg per person per dose. Preferred dosages are 1-500 mgonce daily or BID per person.

Additionally, the compounds of the invention may be administered asprodrugs. As used herein, a “prodrug” of a compound of the invention isa functional derivative of the compound which, upon administration to apatient, eventually liberates the compound of the invention in vivo.Administration of a compound of the invention as a prodrug may enablethe skilled artisan to do one or more of the following: (a) modify theonset of the compound in vivo; (b) modify the duration of action of thecompound in vivo; (c) modify the transportation or distribution of thecompound in vivo; (d) modify the solubility of the compound in vivo; and(e) overcome or overcome a side effect or other difficulty encounteredwith the compound. Typical functional derivatives used to prepareprodrugs include modifications of the compound that are chemically orenzymatically cleaved in vivo. Such modifications, which include thepreparation of phosphates, amides, ethers, esters, thioesters,carbonates, and carbamates, are well known to those skilled in the art.

The compounds of Formula (I) and pharmaceutically acceptable saltsthereof may be used in combination with one or more other agents whichmay be useful in the prevention or treatment of respiratory disease forexample; antigen immunotherapy, anti-histamines, corticosteroids, (e.g.,fluticasone propionate, fluticasone furoate, beclomethasonedipropionate, budesonide, ciclesonide, mometasone furoate,triamcinolone, flunisolide), NSAIDs, leukotriene modulators (e.g.,montelukast, zafirlukast, pranlukast), tryptase inhibitors, IKK2inhibitors, p38 inhibitors, Syk inhibitors, protease inhibitors such aselastase inhibitors, integrin antagonists (e.g., beta-2 integrinantagonists), adenosine A2a agonists, mediator release inhibitors suchas sodium chromoglycate, 5-lipoxygenase inhibitors (zyflo), DP1antagonists, DP2 antagonists, PI3K delta inhibitors, ITK inhibitors, LP(lysophosphatidic) inhibitors or FLAP (5-lipoxygenase activatingprotein) inhibitors (e.g., sodium3-(3-(tert-butylthio)-1-(4-(6-ethoxypyridin-3-yl)benzyl)-5-((5-methylpyridin-2-yl)methoxy)-1H-indol-2-yl)-2,2-dimethylpropanoate),bronchodilators (e.g., muscarinic antagonists, beta-2 agonists),methotrexate, and similar agents; monoclonal antibody therapy such asanti-IgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 andsimilar agents; cytokine receptor therapies e.g. etanercept and similaragents; antigen non-specific immunotherapies (e.g. interferon or othercytokines/chemokines, chemokine receptor modulators such as CCR3, CCR4or CXCR2 antagonists, other cytokine/chemokine agonists or antagonists,TLR agonists and similar agents).

Suitably, for the treatment of asthma, COPD, compounds or pharmaceuticalformulations of the invention may be administered together with ananti-inflammatory agent such as, for example, a corticosteroid, or apharmaceutical formulation thereof. For example, a compound of theinvention may be formulated together with an anti-inflammatory agent,such as a corticosteroid, in a single formulation, such as a dry powderformulation for inhalation. Alternatively, a pharmaceutical formulationcomprising a compound of the invention may be administered inconjunction with a pharmaceutical formulation comprising ananti-inflammatory agent, such as a corticosteroid, either simultaneouslyor sequentially. In one embodiment, a pharmaceutical formulationcomprising a compound of the invention and a pharmaceutical formulationcomprising an anti-inflammatory agent, such as a corticosteroid, mayeach be held in device suitable for the simultaneous administration ofboth formulations via inhalation.

Suitable corticosteroids for administration together with a compound ofthe invention include, but are not limited to, fluticasone furoate,fluticasone propionate, beclomethasone diproprionate, budesonide,ciclesonide, mometasone furoate, triamcinolone, flunisolide andprednisilone. In one embodiment of the invention a corticosteroids foradministration together with a compound of the invention via inhalationincludes fluticasone furoate, fluticasone propionate, beclomethasonediproprionate, budesonide, ciclesonide, mometasone furoate, and,flunisolide.

Suitably, for the treatment of COPD, compounds or pharmaceuticalformulations of the invention may be administered together with one ormore bronchodilators, or pharmaceutical formulations thereof. Forexample, a compound of the invention may be formulated together with oneor more bronchodilators in a single formulation, such as a dry powderformulation for inhalation. Alternatively, a pharmaceutical formulationcomprising a compound of the invention may be administered inconjunction with a pharmaceutical formulation comprising one or morebronchodilators, either simultaneously or sequentially. In a furtheralternative, a formulation comprising a compound of the invention and abronchodilator may be administered in conjunction with a pharmaceuticalformulation comprising a further bronchodilator. In one embodiment, apharmaceutical formulation comprising a compound of the invention and apharmaceutical formulation comprising one or more bronchodilators mayeach be held in device suitable for the simultaneous administration ofboth formulations via inhalation. In a further embodiment, apharmaceutical formulation comprising a compound of the inventiontogether with a bronchodilator and a pharmaceutical formulationcomprising a further bronchodilator may each be held in one or moredevices suitable for the simultaneous administration of bothformulations via inhalation.

Suitable bronchodilators for administration together with a compound ofthe invention include, but are not limited to, P2-adrenoreceptoragonists and anticholinergic agents. Examples of P2-adrenoreceptoragonists, include, for example, vilanterol, salmeterol, salbutamol,formoterol, salmefamol, fenoterol carmoterol, etanterol, naminterol,clenbuterol, pirbuterol, flerbuterol, reproterol, bambuterol,indacaterol, terbutaline and salts thereof, for example the xinafoate(1-hydroxy-2-naphthalenecarboxylate) salt of salmeterol, the sulphatesalt of salbutamol or the fumarate salt of formoterol. Suitableanticholinergic agents include umeclidinium (for example, as thebromide), ipratropium (for example, as the bromide), oxitropium (forexample, as the bromide) and tiotropium (for example, as the bromide).In one embodiment of the invention, a compound of the invention may beadministered together with a β₂-adrenoreceptor agonist, such asvilanterol, and an anticholinergic agent, such as, umeclidinium.

Compositions

The compounds of the invention will normally, but not necessarily, beformulated into pharmaceutical compositions prior to administration to apatient. Accordingly, in another aspect the invention is directed topharmaceutical compositions comprising a compound of the invention and apharmaceutically-acceptable excipient.

The pharmaceutical compositions of the invention may be prepared andpackaged in bulk form wherein a safe and effective amount of a compoundof the invention can be extracted and then given to the patient such aswith powders or syrups. Alternatively, the pharmaceutical compositionsof the invention may be prepared and packaged in unit dosage formwherein each physically discrete unit contains a safe and effectiveamount of a compound of the invention. When prepared in unit dosageform, the pharmaceutical compositions of the invention typically containfrom 1 mg to 1000 mg.

The pharmaceutical compositions of the invention typically contain onecompound of the invention. However, in certain embodiments, thepharmaceutical compositions of the invention contain more than onecompound of the invention. For example, in certain embodiments thepharmaceutical compositions of the invention contain two compounds ofthe invention. In addition, the pharmaceutical compositions of theinvention may optionally further comprise one or more additionalpharmaceutically active compounds.

As used herein, “pharmaceutically-acceptable excipient” means apharmaceutically acceptable material, composition or vehicle involved ingiving form or consistency to the pharmaceutical composition. Eachexcipient must be compatible with the other ingredients of thepharmaceutical composition when commingled such that interactions whichwould substantially reduce the efficacy of the compound of the inventionwhen administered to a patient and interactions which would result inpharmaceutical compositions that are not pharmaceutically acceptable areavoided. In addition, each excipient must of course be of sufficientlyhigh purity to render it pharmaceutically-acceptable.

The compound of the invention and the pharmaceutically-acceptableexcipient or excipients will typically be formulated into a dosage formadapted for administration to the patient by the desired route ofadministration. For example, dosage forms include those adapted for (1)oral administration such as tablets, capsules, caplets, pills, troches,powders, syrups, elixers, suspensions, solutions, emulsions, sachets,and cachets; (2) parenteral administration such as sterile solutions,suspensions, and powders for reconstitution; (3) transdermaladministration such as transdermal patches; (4) rectal administrationsuch as suppositories; (5) inhalation such as dry powders, aerosols,suspensions, and solutions; and (6) topical administration such ascreams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

Suitable pharmaceutically-acceptable excipients will vary depending uponthe particular dosage form chosen. In addition, suitablepharmaceutically-acceptable excipients may be chosen for a particularfunction that they may serve in the composition. For example, certainpharmaceutically-acceptable excipients may be chosen for their abilityto facilitate the production of uniform dosage forms. Certainpharmaceutically-acceptable excipients may be chosen for their abilityto facilitate the production of stable dosage forms. Certainpharmaceutically-acceptable excipients may be chosen for their abilityto facilitate the carrying or transporting of the compound or compoundsof the invention once administered to the patient from one organ, orportion of the body, to another organ, or portion of the body. Certainpharmaceutically-acceptable excipients may be chosen for their abilityto enhance patient compliance.

Suitable pharmaceutically-acceptable excipients include the followingtypes of excipients: diluents, fillers, binders, disintegrants,lubricants, glidants, granulating agents, coating agents, wettingagents, solvents, co-solvents, suspending agents, emulsifiers,sweetners, flavoring agents, flavor masking agents, coloring agents,anticaking agents, hemectants, chelating agents, plasticizers, viscosityincreasing agents, antioxidants, preservatives, stabilizers,surfactants, and buffering agents. The skilled artisan will appreciatethat certain pharmaceutically-acceptable excipients may serve more thanone function and may serve alternative functions depending on how muchof the excipient is present in the formulation and what otheringredients are present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enablethem to select suitable pharmaceutically-acceptable excipients inappropriate amounts for use in the invention. In addition, there are anumber of resources that are available to the skilled artisan whichdescribe pharmaceutically-acceptable excipients and may be useful inselecting suitable pharmaceutically-acceptable excipients. Examplesinclude Remington's Pharmaceutical Sciences 17^(th) ed. (Mack PublishingCompany), The Handbook of Pharmaceutical Additives 1997 (GowerPublishing Limited), and The Handbook of Pharmaceutical Excipients6^(th) ed. (the American Pharmaceutical Association and thePharmaceutical Press).

The pharmaceutical compositions of the invention are prepared usingtechniques and methods known to those skilled in the art. Some of themethods commonly used in the art are described in Remington'sPharmaceutical Sciences 17th ed. (Mack Publishing Company).

In one aspect, the invention is directed to a solid oral dosage formsuch as a tablet or capsule comprising a safe and effective amount of acompound of the invention and a diluent or filler. Suitable diluents andfillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch(e.g. corn starch, potato starch, and pre-gelatinized starch), celluloseand its derivatives (e.g. microcrystalline cellulose), calcium sulfate,and dibasic calcium phosphate. The oral solid dosage form may furthercomprise a binder. Suitable binders include starch (e.g. corn starch,potato starch, and pre-gelatinized starch), gelatin, acacia, sodiumalginate, alginic acid, tragacanth, guar gum, povidone, and celluloseand its derivatives (e.g. microcrystalline cellulose). The oral soliddosage form may further comprise a disintegrant. Suitable disintegrantsinclude crospovidone, sodium starch glycolate, croscarmelose, alginicacid, and sodium carboxymethyl cellulose. The oral solid dosage form mayfurther comprise a lubricant. Suitable lubricants include stearic acid,magnesuim stearate, calcium stearate, and talc.

The compounds may be administered alone or in conjunction with one ormore other therapeutic agents, said agents being selected from the groupconsisting of endothelin receptor antagonists, angiotensin convertingenzyme (ACE) inhibitors, angiotension II receptor antagonists,vasopeptidase inhibitors, vasopressin receptor modulators, diuretics,digoxin, beta blockers, aldosterone antagonists, inotropes, NSAIDS,nitric oxide donors, calcium channel modulators, muscarinic antagonists,steroidal anti-inflammatory drugs, bronchodilators, antihistamines,leukotriene antagonists, HMG-CoA reductase inhibitors, dualnon-selective Padrenoceptor and n1-adrenoceptor antagonists, type-5phosphodiesterase inhibitors, and renin inhibitors.

In another aspect, the invention is directed to a dosage form adaptedfor administration to a patient by inhalation. For example, the compoundof the invention may be inhaled into the lungs as a dry powder, anaerosol, a suspension, or a solution.

Dry powder compositions for delivery to the lung by inhalation typicallycomprise a compound of the invention as a finely divided powder togetherwith one or more pharmaceutically acceptable excipients as finelydivided powders. Pharmaceutically acceptable excipients particularlysuited for use in dry powders are known to those skilled in the art andinclude lactose, starch, mannitol, and mono-, di-, and polysaccharides.

The dry powder compositions for use in accordance with the presentinvention are administered via inhalation devices. As an example, suchdevices can encompass capsules and cartridges of for example gelatin, orblisters of, for example, laminated aluminum foil. In variousembodiments, each capsule, cartridge or blister may contain doses ofcomposition according to the teachings presented herein. Examples ofinhalation devices can include those intended for unit dose ormulti-dose delivery of composition, including all of the devices setforth herein. As an example, in the case of multi-dose delivery, theformulation can be pre-metered (e.g., as in Diskus, see GB2242134, U.S.Pat. Nos. 6,032,666, 5,860,419, 5,873,360, 5,590,645, 6,378,519 and6,536,427 or Diskhaler, see GB 2178965, 2129691 and 2169265, U.S. Pat.Nos. 4,778,054, 4,811,731, 5,035,237) or metered in use (e.g., as inTurbuhaler, see EP 69715, or in the devices described in U.S. Pat. No.6,321,747). An example of a unit-dose device is Rotahaler (see GB2064336). In one embodiment, the Diskus inhalation device comprises anelongate strip formed from a base sheet having a plurality of recessesspaced along its length and a lid sheet peelably sealed thereto todefine a plurality of containers, each container having therein aninhalable formulation containing the compound optionally with otherexcipients and additive taught herein. The peelable seal is anengineered seal, and in one embodiment the engineered seal is a hermeticseal. Preferably, the strip is sufficiently flexible to be wound into aroll. The lid sheet and base sheet will preferably have leading endportions which are not sealed to one another and at least one of theleading end portions is constructed to be attached to a winding means.Also, preferably the engineered seal between the base and lid sheetsextends over their whole width. The lid sheet may preferably be peeledfrom the base sheet in a longitudinal direction from a first end of thebase sheet.

A dry powder composition may also be presented in an inhalation devicewhich permits separate containment of two different components of thecomposition. Thus, for example, these components are administrablesimultaneously but are stored separately, e.g., in separatepharmaceutical compositions, for example as described in WO 03/061743 A1WO 2007/012871 A1 and/or WO2007/068896, as well as U.S. Pat. Nos.8,113,199, 8,161,968, 8,511,304, 8,534,281, 8,746,242 and 9,333,310.

In one embodiment an inhalation device permitting separate containmentof components is an inhaler device having two peelable blister strips,each strip containing pre-metered doses in blister pockets arrangedalong its length, e.g., multiple containers within each blister strip,e.g., as found in ELLIPTA®. Said device has an internal indexingmechanism which, each time the device is actuated, peels opens a pocketof each strip and positions the blisters so that each newly exposed doseof each strip is adjacent to the manifold which communicates with themouthpiece of the device. When the patient inhales at the mouthpiece,each dose is simultaneously drawn out of its associated pocket into themanifold and entrained via the mouthpiece into the patient's respiratorytract. A further device that permits separate containment of differentcomponents is DUOHALER™ of Innovata. In addition, various structures ofinhalation devices provide for the sequential or separate delivery ofthe pharmaceutical composition(s) from the device, in addition tosimultaneous delivery. Aerosols may be formed by suspending ordissolving a compound of the invention in a liquefied propellant.Suitable propellants include halocarbons, hydrocarbons, and otherliquefied gases. Representative propellants include:trichlorofluoromethane (propellant 11), dichlorofluoromethane(propellant 12), dichlorotetrafluoroethane (propellant 114),tetrafluoroethane (HFA-134a), 1,1-difluoroethane (HFA-152a),difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane(HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane, butane,isobutane, and pentane. Aerosols comprising a compound of the inventionwill typically be administered to a patient via a metered dose inhaler(MDI). Such devices are known to those skilled in the art. The aerosolmay contain additional pharmaceutically acceptable excipients typicallyused with multiple dose inhalers such as surfactants, lubricants,cosolvents and other excipients to improve the physical stability of theformulation, to improve valve performance, to improve solubility, or toimprove taste.

Suspensions and solutions comprising a compound of the invention mayalso be administered to a patient via a nebulizer. The solvent orsuspension agent utilized for nebulization may be any pharmaceuticallyacceptable liquid such as water, aqueous saline, alcohols or glycols,e.g., ethanol, isopropyl alcohol, glycerol, propylene glycol,polyethylene glycol, etc. or mixtures thereof. Saline solutions utilizesalts which display little or no pharmacological activity afteradministration. Both organic salts, such as alkali metal or ammoniumhalogen salts, e.g., sodium chloride, potassium chloride or organicsalts, such as potassium, sodium and ammonium salts or organic acids,e.g., ascorbic acid, citric acid, acetic acid, tartaric acid, etc. maybe used for this purpose. Other pharmaceutically acceptable excipientsmay be added to the suspension or solution. The compound of theinvention may be stabilized by the addition of an inorganic acid, e.g.,hydrochloric acid, nitric acid, sulfuric acid and/or phosphoric acid; anorganic acid, e.g., ascorbic acid, citric acid, acetic acid, andtartaric acid, etc., a complexing agent such as EDTA or citric acid andsalts thereof; or an antioxidant such as antioxidant such as vitamin Eor ascorbic acid. These may be used alone or together to stabilize thecompound of the invention. Preservatives may be added such asbenzalkonium chloride or benzoic acid and salts thereof. Surfactant maybe added particularly to improve the physical stability of suspensions.These include lecithin, disodium dioctylsulphosuccinate, oleic acid andsorbitan esters.

EXAMPLES

The following examples illustrate the invention. These examples are notintended to limit the scope of the present invention, but rather toprovide guidance to the skilled artisan to prepare and use thecompounds, compositions, and methods of the present invention. Whileparticular embodiments of the present invention are described, theskilled artisan will appreciate that various changes and modificationscan be made without departing from the spirit and scope of theinvention.

In the Examples:

Chemical shifts are expressed in parts per million (ppm) units. Couplingconstants (J) are in units of hertz (Hz). Splitting patterns describeapparent multiplicities and are designated as s (singlet), d (doublet),t (triplet), q (quartet), dd (double doublet), dt (double triplet), m(multiplet), br (broad).

Flash column chromatography was performed on silica gel.

LCMS data was generated using electrospray positive [ES+ve to give M+H⁺ion]equipped with a C18 column eluting with a gradient of 10%-100%acetonitrile/water containing either 0.05% or 0.1% TFA.

The naming program used is ACD Name Pro 6.02 or the naming functionalityof Chem Draw Ultra 12.0.

The following abbreviations and terms have the indicated meaningsthroughout:

Abbreviation Meaning aq aqueous BH₃ borane Boc tert-butyloxycarbonylBoc₂O di-tert-butyl dicarbonate brine saturated aqueous NaCl solutiont-BuOH tert-butanol Bz benzoyl CDI carbonyldiimidazole CH₂Cl₂ or DCMmethylene chloride CH₃CN or MeCN acetonitrile Cs₂CO₃ cesium carbonateCuI copper iodide DCE 1,2-dichloroethane DEAD diethylazodicarboxylateDIAD diisopropylazodicarboxylate DME dimethyl ether DMFN,N-dimethylformamide DMSO dimethylsulfoxide dppf1,1′-bis(diphenylphosphino)ferrocene ee enantiomeric excess ELSDevaporative light scattering detector Et₃N or TEA triethylamine EtOHethanol Et₂O diethyl ether EtOAc ethyl acetate g gram Grubbs Catalyst,(1,3-Bis(2,4,6-trimethylphenyl)-2- 2^(nd) Generationimidazolidinylidene)dichloro(phenyl-methylene)(tricyclohexylphosphine)ruthenium h, hr hour HCl hydrochloricacid H₂SO₄ sulfuric acid i-PrOH or IPA isopropanol i-Pr₂NEt or DIPEAdiisopropylethylamine or DIEA K₂CO₃ potassium carbonate t-BuOK potassiumtert-butoxide KOH potassium hydroxide L liter LCMS liquidchromatography - mass spectroscopy M molar MC-OsO₄ microencapsulatedosmium tetraoxide m-CPBA metachloroperbenzoic acid Me methyl MeMgBrmethyl magnesium bromide MeOH or CH₃OH methanol MgSO₄ magnesium sulfatemin minute mL milliliter mm millimeter mmol millimole MS mass spectrumMsCl methanesulfonyl chloride MTBE methyl tert-butyl ether N normal NaClsodium chloride Na₂CO₃ sodium carbonate Na₂S₂O₃ sodium thiosulfateNaHCO₃ sodium bicarbonate NaHSO₃ sodium bisulfite NaN₃ sodium azide NaOHsodium hydroxide Na₂SO₃ sodium sulfite Na₂SO₄ sodium sulfate NCSN-chlorosuccinimide NH₃ ammonia NH₄Cl ammonium chloride NH₄OH ammoniumhydroxide NMO N-methylmorpholine N-oxide NMR nuclear magnetic resonancespectroscopy OsO₄ osmium tetraoxide Pd(Cl)₂ palladium dichloridePd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0) Pd(PPh₃)₄tetrakis(triphenylphosphine)palladium(0) PMe₃ trimethyl phosphine PPh₃triphenyl phosphine PS- PPh₃ polymer supported triphenyl phosphine RT orrt room temperature Sat'd saturated SFC supercritical fluidchromatography SiO₂ silica gel SM starting material TBAFtetra-n-butylammonium fluoride TFA trifluoroacetic acid THFtetrahydrofuran TLC thin layer chromatography V volume Zn(CN)₂ zinccyanide

Intermediate 1 (S)-tert-butyl3-hydroxy-4-methylenepyrrolidine-1-carboxylate

Step 1: tert-butyl 3-(benzoyloxy)-4-methylenepyrrolidine-1-carboxylate

A 3 L reaction vessel equipped with an overhead stirrer was charged withtert-butyl 3-hydroxy-4-methylenepyrrolidine-1-carboxylate (158 g, 793mmol, prepared in the manner of Alcaraz, L.; Cridland, A.; Kinchin, E.Org. Lett. 2001, 3, 4051) and Et₃N (170 mL, 1.19 mol) in2-methyltetrahydrofuran (1500 mL). To the solution at 10° C. (internaltemperature) was added benzoylchloride (110 mL, 952 mmol) such that thetemperature remained 10-12° C., followed by DMAP (19.4 g, 159 mmol) andthen the mixture was warmed to ambient temperature and stirredovernight. The mixture was washed with water (1 L) and the organic layerwas dried over MgSO₄, filtered and concentrated to give an amber oil.Flash column chromatography (SiO₂) eluting with a gradient of 10-25%EtOAc in heptane gave pure product fractions which were pooled andconcentrated to give the title compound as a low-melting (56-58° C.)white solid upon standing (210 g, 671 mmol, 85% yield). ¹H NMR (400 MHz,DMSO-d₆) δ: 7.91-8.07 (m, 2H), 7.62-7.71 (m, 1H), 7.47-7.59 (m, 2H),5.73 (dd, J=4.4, 2.9 Hz, 1H), 5.42 (s, 1H), 5.35 (s, 1H), 4.05-4.16 (m,1H), 3.92-4.02 (m, 1H), 3.73-3.85 (m, 1H), 3.50 (dd, J=12.4, 2.6 Hz,1H), 1.41 (br s, 9H).

Step 2: Chiral Resolution: (R) and (S)-tert-butyl3-(benzoyloxy)-4-methylenepyrrolidine-1-carboxylate

Racemic tert-butyl 3-hydroxy-4-methylenepyrrolidine-1-carboxylate (800g) was resolved in 12.5 g batches at a 10 min cycle time via preparativeHPLC (Chiralpak IC, 100×250 mm) eluting with heptanes/IPA (75/25) at aflowrate of 500 mL/min. The respective enantiomer fractions werecombined, concentrated under reduced pressure, and reconcentrated fromEt₂O to give each enantiomer as a faint yellow liquid. R-isomer: 380 g,chiral HPLC: 96.2% ee, ¹H NMR (400 MHz, CD₃OD) δ: 8.03 (d, J=7.3 Hz,2H), 7.60-7.68 (m, 1H), 7.47-7.54 (m, 2H), 5.81 (br s, 1H), 5.50 (br s,1H), 5.36 (br s, 1H), 4.17-4.25 (m, 1H), 4.01-4.10 (m, 1H), 3.83 (br s,1H), 3.64 (dd, J=12.5, 1.8 Hz, 1H), 1.51 (br s, 9H). MS (m/z) 304(M+H⁺). S-Isomer: 352 g, chiral HPLC: 98% ee, ¹H NMR (400 MHz, CD₃OD) δ:7.99-8.06 (m, 2H), 7.60-7.67 (m, 1H), 7.47-7.54 (m, 2H), 5.80 (br s,1H), 5.49 (br s, 1H), 5.36 (br s, 1H), 4.16-4.25 (m, 1H), 4.01-4.09 (m,1H), 3.83 (br s, 1H), 3.64 (dd, J=12.4, 2.1 Hz, 1H), 1.51 (s, 9H). MS(m/z) 303.9 (M+H⁺).

Step 3: (S)-tert-butyl 3-hydroxy-4-methylenepyrrolidine-1-carboxylate

KOH pellets (61.4 g, 1.09 mol) were added to MeOH (200 mL) at rt. Thewarm/hot solution was cooled in an ice bath to reduce the temperature to25° C. While chilled in the ice bath, a solution of the (S)-tert-butyl3-(benzoyloxy)-4-methylenepyrrolidine-1-carboxylate (83 g, 274 mmol) inMeOH (100 mL) was added in one portion. The resulting solution wasstirred at rt for 1 hr. The suspension was filtered through celite andthe cake rinsed with MeOH (60 mL) and MTBE (100 mL). The filtrate wasconcentrated under reduced pressure and the solid residue dissolved inwater (250 mL). The aqueous phase was reconcentrated under reducedpressure to remove the last traces of MeOH and extracted with MTBE(3×330 mL). The combined organics were washed with brine (30 mL), driedover Na₂SO₄, filtered, and concentrated under reduced pressure to givethe title compound as a light brownish oil (55.0 g, 95% yield). ¹H NMR(400 MHz, CD₃OD) δ: 5.27 (br s, 1H), 5.14 (br s, 1H), 4.54-58 (m, 1H),4.03-4.12 (m, 1H), 3.91-3.99 (br m, 1H), 3.58-3.68 (m, 1H), 3.21-3.28(1H, partially hidden by solvent peak), 1.49 (s, 9H). MS (m/z) 199.9(M+H⁺).

Inversion of Stereochemistry (S)-tert-butyl3-(benzoyloxy)-4-methylenepyrrolidine-1-carboxylate

Step 1: (R)-tert-butyl 3-hydroxy-4-methylenepyrrolidine-1-carboxylate

KOH pellets (66.0 g, 1.18 mol) were added to MeOH (250 mL) at rt. Thewarm/hot solution was cooled in an ice bath to reduce the temperature to25° C. While chilled in the ice bath, a solution of the (R)-tert-butyl3-(benzoyloxy)-4-methylenepyrrolidine-1-carboxylate (102 g, 336 mmol) inMeOH (150 mL) was added in one portion. The resulting solution wasstirred at rt for 1 hr. The suspension was filtered through celite andthe cake rinsed with MeOH (100 mL) and MTBE (150 mL). The filtrate wasconcentrated under reduced pressure and the solid residue dissolved inwater (300 mL). The aqueous phase was reconcentrated under reducedpressure to remove the last traces of MeOH and extracted with MTBE(3×330 mL). The combined organics were washed with brine (30 mL), driedover Na₂SO₄, filtered, and concentrated under reduced pressure to givethe title compound as a light brownish syrup (68.7 g, 103% yield). ¹HNMR (400 MHz, CD₃OD) δ: 5.26 (br s, 1H), 5.15 (br s, 1H), 4.56 (br s,1H), 4.01-4.14 (m, 1H), 3.97 (d, J=4.8 Hz, 1H) 3.64 (br s, 1H),3.23-3.28 (1H, partially hidden by solvent peak), 1.49 (s, 9H). MS (m/z)199.9 (M+H⁺).

Step 2: (S)-tert-butyl3-(benzoyloxy)-4-methylenepyrrolidine-1-carboxylate

To a 2L RB 3-neck flask fitted with a mechanical stirrer, thermometerand under nitrogen was added THE (700 mL) followed by (R)-tert-butyl3-hydroxy-4-methylenepyrrolidine-1-carboxylate (37.0 g, 186 mmol),benzoic acid (27.2 g, 223 mmol) and PS-PPh₃ (3 mmol/g) (105 g, 316mmol). Neat diisopropylazodicarboxylate (46.0 g, 223 mmol) was addeddropwise and portionwise via an addition funnel over a 1 h period suchthat the internal temperature never rose above 10° C. After addition wascompleted, the mixture was stirred in the ice bath for 30 min. The icebath was removed and the reaction allowed to warm for 2 h. To themixture at rt was added 2.5 g DIAD and 10 g of the PPh₃-solid phasebeads and the mixture was stirred at rt for an additional 20 h. Thesuspension was filtered, and the resins were washed with EtOAc (4×100mL). The filtrate was concentrated under reduced pressure to give acrude brownish oil (108 g). The oil was taken up in MTBE (100 mL) toyield a suspension, which was filtered to remove an off-white solid. Thefiltrate was concentrated and purified by flash column chromatography(SiO₂) eluting with a gradient of 0-50% EtOAc in hexanes. The productfractions were pooled and concentrated under reduced pressure to givethe title compound as a clear pale yellowish oil (39.17 g, 70% yield).Chiral purity: 97.8% ee. ¹H NMR (400 MHz, CD₃OD) δ: 8.02 (d, J=8.0 Hz,2H), 7.59-7.66 (m, 1H), 7.46-7.53 (m, 2H), 5.80 (br s, 1H), 5.49 (br s,1H), 5.35 (br s, 1H), 4.16-4.24 (m, 1H), 4.01-4.09 (m, 1H), 3.82 (br s,1H), 3.64 (d, J=12.5 Hz, 1H), 1.50 (s, 9H). MS (m/z) 304.1 (M+H⁺). Thiscompound can be hydrolyzed to give intermediate 1 as described above.

Intermediate 2 (S)-tert-butyl3-methylene-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate

(S)-tert-butyl3-methylene-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate

To a cooled solution of (S)-tert-butyl3-hydroxy-4-methylenepyrrolidine-1-carboxylate (20.4 g, 103 mmol) in DCM(200 mL) was added Et₃N (21.4 mL, 154 mmol) at 0° C., followed by adropwise addition of methanesulfonyl chloride (11.9 mL, 154 mmol) andthe reaction mixture was stirred at rt for 30 min. The reaction mixturewas diluted with DME, washed with H₂O, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford the title compound as abrown oil (28.8 g, 100% yield). The title compound was used as is insubsequent reactions.

Intermediate 3

Intermediate 3 may be prepared according to procedures detailed inMaguire, R. J.; Mulzer, J.; Bats, J. W. J. Org. Chem. 1996, 61, 6936.

Intermediate 4 2-Chloro-5-mercaptobenzonitrile

Step 1: O-(4-chloro-3-cyanophenyl) dimethylcarbamothioate

2-Chloro-5-hydroxybenzonitrile (700 mg, 4.56 mmol) was suspended inCHCl₃ (15 ml) and treated with DMAP (55 mg, 0.45 mmol), TEA (1.9 ml,13.7 mmol) and dimethylcarbamothioic chloride (676 mg, 5.47 mmol). Themixture was then heated at 45° C. overnight before being diluted withDCM (100 mL), washed with water (2×50 mL), dried over MgSO₄, filteredand concentrated under reduced pressure. The crude product was purifiedby flash column chromatography (SiO₂) eluting with a gradient of 0-30%EtOAc in hexanes. The desired product fractions were pooled andconcentrated to give the title compound as a white solid (965 mg, 88%yield). MS (m/z) 240.8 (M+H⁺).

Step 2: S-(4-chloro-3-cyanophenyl) dimethylcarbamothioate

O-(4-chloro-3-cyanophenyl) dimethylcarbamothioate (965 mg, 4.01 mmol)was heated at 200° C. for 3.5 h. The reaction mixture was cooled and thecrude material used as is in step 3 (965 mg, 100% yield). MS (m/z) 240.8(M+H⁺).

Step 3: 2-Chloro-5-mercaptobenzonitrile

KOH (400 mg, 7.2 mmol) was added to a solution ofS-(4-chloro-3-cyanophenyl) dimethylcarbamothioate (965 mg, 4.0 mmol) inMeOH (10 mL) and THE (7.5 mL) and the reaction mixture was allowed tostir at rt for 6 days. The reaction mixture was concentrated under astream of nitrogen at 40° C. The residue was treated with EtOAc (100 mL)and 0.1 M HCl (aq) was added to adjust to pH=2. The organic layer waswashed with water and brine, dried over MgSO₄, filtered and concentratedunder reduced pressure. The crude product was purified by flash columnchromatography (SiO₂) eluting with a gradient of 0-40% EtOAc in hexanes.The desired product fractions were pooled and concentrated to give thetitle compound as a white solid (383 mg, 56% yield). ¹H NMR (400 MHz,DMSO-d₆) δ: 7.92 (br s, 1H), 7.55-7.71 (m, 2H), 6.10 (br s, 1H). MS(m/z) 169.9 (M+H⁺).

INTERMEDIATES 5-9 were prepared from the appropriate phenol by the threestep method analogous to that described for intermediate 4.

¹H NMR or MS (m/z) # Name Structure (M + H⁺) 5 2,6-difluoro- 4-mercapto-benzonitrile

¹H NMR (400 MHz, CDCl₃) δ: 6.95 (s, 1H), 6.92-6.94 (m, 1H), 3.90 (s, 1H)6 2-fluoro-4- mercapto- benzonitrile

¹H NMR (400 MHz, CDCl₃) δ: 7.43-7.53 (m, 1H), 7.12 (d, J = 8.5 Hz, 2H),3.81 (s, 1H) 7 2,5-difluoro- 4-mercapto- benzonitrile

Used as is, not characterized 8 2-chloro-4- mercapto- benzonitrile

170.0 9 6-(trifluoro- methyl)pyridine- 3-thiol

179.8

Intermediate 10 5-Mercaptopicolinonitrile

5-Mercaptopicolinonitrile

A mixture of Na₂S (2.25 g, 28.8 mmol) in deoxygenated (nitrogen sparged)DMF (75 mL) was treated with solution of 5-fluoropicolinonitrile (3.22g, 26.3 mmol) in deoxygenated DMF (25 mL) and stirred at rt for 19 h.The mixture was diluted with 1 N NaOH (aq) (50 mL) and extracted withDCM (2×100 mL) breaking up any emulsions that formed with brine. The pHof the aqueous phase was adjusted to ˜4 with 1 N HCl (aq) (50 mL) andthe precipitate that formed was collected by filtration and dried togive the title compound as a tan powder (1.48 g, 41% yield). ¹H NMR (400MHz, DMSO-d₆) δ: 8.67 (s, 1H), 7.98 (d, J=8.3 Hz, 1H), 7.86 (d, J=8.3Hz, 1H). MS (m/z) 136.7 (M+H⁺).

Intermediate 11 6-(Trifluoromethyl)pyridine-3-thiol

Step 1: O-ethyl S-(6-(trifluoromethyl)pyridin-3-yl) carbonodithioate

To a solution of p-toluenesulfonic acid monohydrate (30 g, 160 mmol) inCH₃CN (100 mL) and water (10 mL) was added a solution of6-(trifluoromethyl)pyridin-3-amine (10 g, 62 mmol) in CH₃CN (40 mL)followed by a solution of potassium O-ethyl carbonodithioate (20 g, 125mmol) and sodium nitrite (8 g, 120 mmol) in water (50 mL). The reactionmixture was stirred at rt for 2 h, then diluted with water and extractedwith EtOAc (2×100 mL). The combined organic layers were washed withNaHCO₃ and water, dried over MgSO₄, filtered and concentrated. The crudeproduct was purified by flash column chromatography (SiO₂) eluting witha gradient of 0-5% EtOAc in hexanes to give the title compound as alight yellow oil (13.5 g, 82% yield). MS (m/z) 267.8 (M+H⁺).

Step 2: 6-(Trifluoromethyl)pyridine-3-thiol

A mixture of O-ethyl S-(6-(trifluoromethyl)pyridin-3-yl)carbonodithioate (13.5 g, 50.5 mmol) and 1 N NaOH (aq) (100 ml, 100mmol) in ethanol (100 mL) was stirred at 80° C. for 40 min. The reactionmixture was cooled, concentrated under reduced pressure, diluted withwater and extracted with DCM. The aqueous layer was then neutralizedwith acetic acid and the resulting mixture was extracted with DCM. Theorganic extract was dried over anhydrous MgSO₄ and concentrated to givethe title compound as a colorless oil (6.5 g, 72% yield). ¹H NMR (400MHz, CDCl₃) δ: 8.60 (s, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.3 Hz,1H), 3.63 (s, 1H). MS (m/z) 179.8 (M+H⁺).

Intermediate 12

To a suspension of sodium hydrogen sulfide (monohydrate) (365 mg, 6.51mmol) in ethanol (9 mL) was added 5-bromo-2-(trifluoromethyl)pyrimidine(603 mg, 2.66 mmol) and the reaction mixture was refluxed for 18 h. Thereaction mixture was concentrated under reduced pressure and water (10mL) was added. The aqueous phase was adjusted to pH˜3-4 with 1 N HCl(aq) and extracted with EtOAc (2×30 mL). The organic extracts werecombined, washed with brine, dried over Na₂SO₄, filtered andconcentrated to give the title compound as a light brown oil (319 mg,67% yield). ¹H NMR (400 MHz, DMSO-d₆) δ: 9.20 (s, 2H), 4.44-5.48 (br s,1H). MS (m/z) 202.9 (M+Na⁺).

Intermediate 13 6-(difluoromethoxy)pyridine-3-sulfonyl chloride

Step 1: 5-(benzylthio)-2-(difluoromethoxy)pyridine

A mixture of benzyl mercaptan (0.528 mL, 4.46 mmol),5-bromo-2-(difluoromethoxy)pyridine (1 g, 4.46 mmol), xantphos (0.258 g,0.446 mmol), and DIPEA (1.56 mL, 8.93 mmol) in toluene (25 mL) undernitrogen was treated with Pd₂(dba)₃ (0.204 g, 0.223 mmol) and heated at110° C. overnight. The reaction mixture was cooled and water was added.The mixture was filtered and the filtrate was extracted with EtOAc. Theorganic layer was washed with sat'd NaHCO₃ (aq) and brine and dried overNa₂SO₄, filtered and concentrated. The residue was purified by flashcolumn chromatography (SiO₂) eluting with a gradient of 0-100% EtOAc inhexanes. The product fractions were pooled and concentrated to give thetitle compound as a yellow oil (970 mg, 81% yield). MS (m/z) 268.2(M+H⁺).

Step 2: 6-(difluoromethoxy)pyridine-3-sulfonyl chloride

To a solution of 5-(benzylthio)-2-(difluoromethoxy)pyridine (860 mg, 3.2mmol) in acetic acid (10 mL) and water (3.3 mL) was added NCS (1.7 g, 13mmol) and the reaction mixture was stirred at rt for 1.5 hours. Thereaction mixture was concentrated under reduced pressure, sat'd NaHCO₃(aq) was added and the mixture was extracted with EtOAc. The organiclayer was washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography (SiO₂) eluting with a gradient of 0-100% EtOAc inhexanes. The product fractions were pooled and concentrated to give thetitle compound as a clear oil (900 mg, 80% yield). ¹H NMR (400 MHz,DMSO-d₆) δ: 8.40 (d, J=1.8 Hz, 1H), 8.03 (dd, J=8.5, 2.3 Hz, 1H),7.53-7.94 (m, 1H), 7.01-7.09 (m, 1H).

INTERMEDIATES 14-16 were prepared by the 2 step method analogous to thatdescribed for intermediate 13. The appropriate ArX used in the firststep was commercially available as the bromide (X═Br) or chloride(X═Cl). Conversion of the thioether to the sulfonyl chloride in thesecond step can alternatively be accomplished by bubbling Cl₂ gas into asolution of the thioether in formic acid.

¹H NMR or MS # Name Structure (m/z) (M + H⁺) 14 2-chloro-4-(difluoro-methyl)benzene-1- sulfonyl chloride

260.8 15 2-(difluoro- methoxy)pyridine- 3-sulfonyl chloride

244.0 16 4-chloro-2- methoxybenzene- 1-sulfonyl chloride

Used as is, not characterized

Intermediate 17 2-fluoro-4-(trifluoromethyl)benzene-1-sulfonyl chloride

2-fluoro-4-(trifluoromethyl)benzene-1-sulfonyl chloride

2-fluoro-4-(trifluoromethyl)aniline (1 g, 5.6 mmol) was added to amixture of conc. HCl (4 mL) and acetic acid (3 mL). The mixture wascooled to 10° C. and a solution of sodium nitrite (0.42 g, 6.1 mmol) ina minimum amount of water was added dropwise and the mixture stirred at10° C. for 45 min to form the diazonium salt. In a separate reactionflask, sulfur dioxide (0.36 g, 5.6 mmol) was bubbled into acetic acid (8mL) until saturation. Copper(I) chloride (0.17 g, 1.7 mmol) was addedand stirred until the mixture turned green. The flask was cooled in anice bath, the diazonium salt mixture was added dropwise and the reactionmixture was allowed to warm to rt overnight with stirring. The reactionmixture was poured into ice, the resulting solid collected byfiltration, washed well with water and dried to give the title compound(0.70 g, 48% yield). ¹H NMR (400 MHz, CDCl₃) δ: 8.17 (t, J=7.4 Hz, 1H),7.61-7.71 (m, 2H).

INTERMEDIATE 18 was prepared from the appropriate aniline by the onestep method analogous to that described for intermediate 17.

# Name Structure ¹H NMR 18 4-cyano-2- (trifluoro- methyl)benzene-1-sulfonyl chloride

¹H NMR (400 MHz, DMSO-d₆) δ: 8.23 (d, J = 8.0 Hz, 1H), 8.19 (s, 1H),8.11 (d, J = 8.0 Hz, 1H)

Intermediate 19 4-cyano-2-cyclopropoxybenzene-1-sulfonyl Chloride

Step 1: O-(4-cyano-2-cyclopropoxyphenyl) dimethylcarbamothioate

3-Cyclopropoxy-4-hydroxybenzonitrile (0.90 g, 5.1 mmol) and DMAP (0.063g, 0.51 mmol) were dissolved in CHCl₃ (17 ml). TEA (2.1 ml, 15 mmol) wasadded followed by dimethylcarbamothioic chloride (0.64 g, 5.2 mmol) andthe reaction mixture was heated at 45° C. for 17 h. The reaction mixturewas cooled, concentrated under reduced pressure and the crude productwas purified by flash column chromatography (SiO₂) eluting with agradient of 0-100% MTBE in hexanes. The desired fractions were pooledand concentrated under reduced pressure to give the title compound as ayellow oil (1.15 g, 85% yield. MS (m/z) 262.8 (M+H⁺).

Step 2: S-(4-cyano-2-cyclopropoxyphenyl) dimethylcarbamothioate

O-(4-cyano-2-cyclopropoxyphenyl) dimethylcarbamothioate (1.15 g, 4.36mmol) was heated at 200° C. for 4 h before being cooled, treated withDCM and concentrated to near dryness under a stream of nitrogen at 50°C. The crude product was purified by flash column chromatography (SiO₂)eluting with a gradient of 0-10% MeOH in DCM. The desired fractions werepooled and concentrated under reduced pressure to give the titlecompound as a red oil that solidified on standing (0.89 g, 78% yield).MS (m/z) 262.9 (M+H⁺).

Step 3: 4-cyano-2-cyclopropoxybenzene-1-sulfonyl chloride

S-(4-cyano-2-cyclopropoxyphenyl) dimethylcarbamothioate (0.89 g, 3.40mmol) was dissolved in MeOH (5 ml) and THE (5 ml). NCS (1.4 g, 10 mmol)was added and the reaction mixture was stirred at rt for 30 min. Themixture was concentrated under reduced pressure to near dryness andpurified by flash column chromatography (SiO₂) eluting with a gradientof 0-50% MTBE in hexanes. The desired fractions were pooled andconcentrated under reduced pressure to give the title compound as aclear oil that became a white solid on standing (466 mg, 53% yield). MS(m/z) 258.1 (M+H⁺).

INTERMEDIATE 20 was prepared from the appropriate phenol by the 3 stepmethod analogous to that described for intermediate 19.

# Name Structure MS (m/z) (M + H⁺) 20 4-cyano-2- ethoxybenzene-1-sulfonyl chloride

246.0

Intermediate 21 4-cyano-2-(difluoromethyl)benzene-1-sulfonyl chloride

Step 1: 4-bromo-3-(difluoromethyl)benzonitrile

4-Bromo-3-formylbenzonitrile (1.04 g, 4.94 mmol) was dissolved DCM (59.5ml), treated with deoxofluor (2.7 ml, 14.8 mmol) and heated at 45° C.for 1.5 h. The reaction mixture was cooled in an ice/water bath andcarefully quenched with sat'd NaHCO₃ (aq). The layers were separated,and the aqueous phase was extracted with DCM. The organic layers werecombined and concentrated under reduced pressure. The crude product waspurified by flash column chromatography (SiO₂) eluting with a gradientof 0-75% MTBE in hexanes. The desired product fractions were pooled andconcentrated under reduced pressure to give the title compound as awhite solid (980 mg, 85% yield). MS (m/z) 231.9 (M+H⁺).

Step 2: 4-(benzylthio)-3-(difluoromethyl)benzonitrile

4-bromo-3-(difluoromethyl)benzonitrile (980 mg, 4.2 mmol), xantphos (82mg, 0.14 mmol) and Pd₂(dba)₃ (97 mg, 0.11 mmol) were combined in1,4-dioxane (30 mL). DIPEA (1.5 mL, 8.5 mmol) and benzyl mercaptan (600μl, 5.1 mmol) were added and the reaction mixture was heated at 100° C.for 1 h. The mixture was concentrated and the crude product was purifiedby flash column chromatography eluting with a gradient of 0-35% MTBE inhexanes. The desired product fractions were pooled and concentratedunder reduced pressure to give the title compound as an orange oil (1.1g, 100% yield). MS (m/z) 276.1 (M+H⁺).

Step 3: 4-cyano-2-(difluoromethyl)benzene-1-sulfonyl chloride

4-(benzylthio)-3-(difluoromethyl)benzonitrile (1.1 g, 4.2 mmol) wasdissolved in THE (6 mL) and MeOH (6 mL), NCS (1.70 g, 13 mmol) was addedand the reaction mixture was stirred at rt for 30 min. The mixture wasconcentrated under reduced pressure and purified by flash columnchromatography (SiO₂) eluting with a gradient of 0-40% MTBE in hexanes.The desired product fractions were pooled and concentrated under reducedpressure to give the title compound as a white solid (540 mg, 51%yield). ¹H NMR (400 MHz, CDCl₃) δ: 8.34 (d, J=8.3 Hz, 1H), 8.29 (s, 1H),8.06 (d, J=8.3 Hz, 1H), 7.40-7.73 (m, 1H).

INTERMEDIATE 22 was prepared from the appropriate benzaldehyde by the 3step method analogous to that described for intermediate 21.

MS (m/z) # Name Structure (M + H⁺) 22 2-chloro-4-(difluoromethyl)benzene-1- sulfonyl chloride

260.8

Example 13-chloro-4-(((3R,4S)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile

Step 1: (R)-tert-butyl3-((5-chloropyridin-2-yl)thio)-4-methylenepyrrolidine-1-carboxylate

(S)-tert-butyl3-methylene-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (22.2 g, 80mmol) was dissolved in DMF (300 mL) and 5-chloropyridine-2-thiol (11.7g, 80 mmol) was added followed by K₂CO₃ (16.7 g, 120 mmol). The reactionmixture thickened on stirring and was complete after 1 h at rt. Themixture was poured into ice water and extracted with 400 mL of ethylacetate/hexanes (1:1 V/V). The organic extract was washed with water(2×400 mL), dried over MgSO₄, filtered, and concentrated to give a crudeproduct. Purification was carried out by flash column chromatography(SiO₂) eluting with a gradient of 0-15% EtOAc in hexanes. Concentrationof the pooled product fractions gave the title compound as a slightlyyellow oil (21.2 g, 81% yield). MS (m/z) 327.1 (M+H⁺).

Step 2: (R)-tert-butyl3-((5-chloropyridin-2-yl)sulfonyl)-4-methylenepyrrolidine-1-carboxylate

A flask containing a solution of (R)-tert-butyl3-((5-chloropyridin-2-yl)thio)-4-methylenepyrrolidine-1-carboxylate (21g, 64 mmol) in DCM (200 mL) was cooled in an ice/acetone bath. m-CPBA(59 g, 260 mmol) was divided into two equal portions and the portionswere added 20 min apart, and the mixture was stirred for 1.5 h. Themixture was quenched with 10% Na₂S₂O₃ (aq) (300 mL) and extracted withDCM (300 mL). The organic extract was washed with sat'd NaHCO₃ (aq)(2×300 mL), dried over MgSO₄, filtered and concentrated. The crudeproduct was purified by flash column chromatography (SiO₂) eluting witha gradient of 0-10% EtOAc in DCM. Concentration of the pooled productfractions gave the title compound as white solid (13.6 g, 59% yield). MS(m/z) 302.9 (M+H⁺).

Step 3: (3R,4S)-tert-butyl4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidine-1-carboxylate

To a solution of (R)-tert-butyl3-((5-chloropyridin-2-yl)sulfonyl)-4-methylenepyrrolidine-1-carboxylate(13.5 g, 37.6 mmol) in THE (100 mL) was added OSO₄ (2.5% in t-BuOH) (24mL, 1.9 mmol), followed by NMO (50% wt in water, 19.5 mL, 94 mmol) andthe reaction mixture was stirred at rt for 2 h. The mixture was treatedwith saturated Na₂SO₃ (aq) (120 mL) and extracted with ethyl acetate.The organic extract was washed with brine, dried over MgSO₄, filteredand concentrated. The crude product was purified by flash columnchromatography eluting with a gradient of 0-40% ethyl acetate/ethanol(3:1 V) in hexanes. Concentration of the combined product fractions gavethe title compound as white solid (14.5 g, 98% yield). ¹H NMR (400 MHz,DMSO-d₆) δ: 8.91 (s, 1H), 8.33 (d, J=7.8 Hz, 1H), 8.10 (d, J=8.3 Hz,1H), 5.59 (d, J=16.1 Hz, 1H), 4.75-4.85 (m, 1H), 4.13-4.24 (m, 1H),3.55-3.75 (m, 4H), 3.45 (d, J=11.0 Hz, 1H), 3.18-3.29 (m, 1H), 1.40 (s,9H). MS (m/z) 393.0 (M+H⁺).

Step 4:3-chloro-4-(((3R,4S)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile

A mixture of (3R,4S)-tert-butyl4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidine-1-carboxylate(14.5 g, 36.9 mmol) in DCM (60 mL) and TFA (60 mL, 780 mmol) was stirredat rt for 20 min. The mixture was concentrated and the residue dilutedwith THE (100 mL) and basified with sat'd NaHCO₃ (aq). To the mixturewas added dropwise a solution of 2-chloro-4-cyanobenzene-1-sulfonylchloride (10.5 g, 44.3 mmol) in THE (100 mL) and the mixture was stirredat rt for 30 min before being diluted with brine and extracted withEtOAc. The organic extract was washed with brine and dried over MgSO₄,filtered and concentrated. The crude product was purified by flashcolumn chromatography eluting with a gradient of 0-40% ethylacetate/ethanol (3:1 V) in hexanes. The product fractions were pooledand concentrated to give the title compound as a colorless semi-solid.¹H NMR (400 MHz, DMSO-d₆) δ: 8.90 (d, J=2.0 Hz, 1H), 8.37 (d, J=1.5 Hz,1H), 8.33 (dd, J=8.5, 2.4 Hz, 1H), 8.11-8.16 (m, 1H), 8.02-8.08 (m, 2H),5.81 (s, 1H), 4.92 (t, J=5.6 Hz, 1H), 4.30 (dd, J=7.6, 3.0 Hz, 1H),3.88-3.96 (m, 1H), 3.79 (dd, J=11.6, 3.0 Hz, 1H), 3.54-3.71 (m, 3H),3.33-3.38 (1H, partially hidden by solvent peak). MS (m/z) 492.0 (M+H⁺).

Example 23-chloro-4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile

Step 1: (R)-tert-butyl3-((4-chlorophenyl)thio)-4-methylenepyrrolidine-1-carboxylate

To a solution of (S)-tert-butyl3-methylene-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (8.85 g,31.9 mmol) in DMF (177 mL) was added K₂CO₃ (8.82 g, 63.8 mmol) followedby 4-chlorobenzenethiol (5.54 g, 38.3 mmol) and the reaction mixture wasstirred at rt for 16 h before being diluted with water and extractedwith EtOAc (4 times). The combined organic layers were concentratedunder reduced pressure and the crude product was purified by flashcolumn chromatography (SiO₂) eluting with a gradient of 0-40% MTBE inhexanes. The desired fractions were pooled, concentrated under reducedpressure and dried under high vacuum to give the title compound as awhite solid (5.14 g, 49% yield). MS (m/z) 326.2 (M+H⁺).

Step 2: (3R,4S)-tert-butyl4-((4-chlorophenyl)thio)-3-hydroxy-3-(hydroxymethyl)pyrrolidine-1-carboxylateand (3S,4S)-tert-butyl4-((4-chlorophenyl)thio)-3-hydroxy-3-(hydroxymethyl)pyrrolidine-1-carboxylate

(R)-tert-butyl3-((4-chlorophenyl)thio)-4-methylenepyrrolidine-1-carboxylate (5.14 g,15.7 mmol) was dissolved in THE (150 mL). NMO (50% in water, 6.5 mL,31.5 mmol) was added followed by OSO₄ (2.5% in t-BuOH) (10 mL, 0.80mmol). The reaction mixture was stirred to ensure mixing then placed ina 0° C. freezer overnight (16 h) without stirring. The mixture wasallowed to warm to rt with stirring over 4 h and then poured into aseparatory funnel containing sat'd Na₂SO₃ (40 mL). The solution wasallowed to sit for several hours, diluted with brine and the layersseparated. The aqueous layer was further extracted with EtOAc (3×). Thecombined organic fractions were concentrated under reduced pressure, andthe crude product was purified by flash column chromatography (SiO₂)eluting with a gradient of 0-45% EtOAc in hexanes. The desired fractionswere pooled, concentrated under reduced pressure, and dried under highvacuum to give the title compound as a white solid foam (2.88 g, 51%yield). This sample contained an estimated 80/20 mixture of trans/cisisomers (by NMR). The mixture can be separated into its individual transand cis isomers in the final step. ¹H NMR (400 MHz, DMSO-d₆) δ:7.11-7.70 (m, 4H), 5.29 (s, 1H), 4.87 (t, J=5.1 Hz, 1H), 3.68-3.82 (m,2H), 3.54 (d, J=5.0 Hz, 2H), 3.46 (dd, J=10.9, 4.6 Hz, 1H), 3.22-3.29(m, 1H), 3.12-3.21 (m, 1H), 1.38 (m, 9H). MS (m/z) 360.1 (M+H⁺).

Step 3: (3R,4S)-tert-butyl4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidine-1-carboxylateand (3S,4S)-tert-butyl4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidine-1-carboxylate

A mixture of (3R,4S)-tert-butyl4-((4-chlorophenyl)thio)-3-hydroxy-3-(hydroxymethyl)pyrrolidine-1-carboxylateand (3S,4S)-tert-butyl4-((4-chlorophenyl)thio)-3-hydroxy-3-(hydroxymethyl)pyrrolidine-1-carboxylate(2.9 g, 8.0 mmol) was dissolved in DCM (160 mL) and cooled in anice/water bath. m-CPBA (3.87 g, 16.8 mmol) was added portionwise, andthe reaction mixture was stirred over the weekend (67 h). The mixturewas concentrated and the crude product purified by flash columnchromatography (SiO₂) eluting with a gradient of 0-50% EtOAc in hexanes.The desired fractions were pooled, concentrated under reduced pressureand dried under high vacuum to give the title compound as a white solid(1.12 g, 2.72 mmol, 34% yield). ¹H NMR (400 MHz, DMSO-d₆) δ: 7.91 (d,J=8.5 Hz, 2H), 7.78 (d, J=8.3 Hz, 2H), 5.54 (d, J=9.3 Hz, 1H), 4.86 (d,J=4.3 Hz, 1H), 3.98 (d, J=4.3 Hz, 1H), 3.71-3.79 (m, 1H), 3.44-3.70 (m,4H), 3.17-3.29 (m, 1H), 1.36-1.42 (m, 9H). MS (m/z) 392.1 (M+H⁺).

Step 4:(3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol,Hydrochloride and(3S,4S)-4-((4-chlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol,Hydrochloride

To a mixture of (3R,4S)-tert-butyl4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidine-1-carboxylateand (3S,4S)-tert-butyl4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidine-1-carboxylate(1.12 g, 2.86 mmol) in 1,4-dioxane (14 mL) was added 4 N HCl in dioxane(14 mL, 56.0 mmol) under an atmosphere of nitrogen. After 2 h, a secondportion of 4 N HCl in dioxane (8 mL, 32.0 mmol) was added and stirringcontinued for 6 h. The reaction mixture was concentrated under reducedpressure, then under high vacuum overnight to give the title compound asa white solid (920 mg, 2.80 mmol, 98% yield). MS (m/z) 291.9 (M+H⁺).

Step 5:3-Chloro-4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile

The mixture of(3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol,Hydrochloride and(3S,4S)-4-((4-chlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol,Hydrochloride (100 mg, 0.31 mmol) was partitioned between THE (1.9 mL)and sat'd NaHCO₃ (aq) (1.3 mL). 2-chloro-4-cyanobenzene-1-sulfonylchloride (86 mg, 0.366 mmol) was suspended in THE (2 mL) and addeddropwise to the well stirred mixture. After 1 h, the layers wereseparated and the aqueous layer was extracted with EtOAc. The combinedorganic layers were concentrated under a stream of nitrogen at 50° C.The crude product was purified by flash column chromatography (SiO₂)eluting with a gradient of 0-80% EtOAc in hexanes. The trans isomerfractions were pooled, concentrated under reduced pressure and driedunder high vacuum, to give the title compound as a white foam (115 mg,0.227 mmol, 75% yield). ¹H NMR (400 MHz, DMSO-d₆) δ: 8.38 (d, J=1.0 Hz,1H), 8.11-8.15 (m, 1H), 8.05-8.10 (m, 1H), 7.82-7.87 (m, 2H), 7.75-7.79(m, 2H), 5.79 (s, 1H), 4.99 (t, J=5.4 Hz, 1H), 4.14 (dd, J=7.3, 3.3 Hz,1H), 3.72-3.84 (m, 2H), 3.62-3.70 (m, 2H), 3.57 (dd, J=11.4, 3.3 Hz,1H), 3.37 (d, J=9.9 Hz, 1H). MS (m/z) 490.9 (M+H⁺).

The following compounds were prepared using procedures analogous tothose described in Example 2 using appropriately substituted startingmaterials. As is appreciated by those skilled in the art, theseanalogous examples may involve variations in general reactionconditions.

MS (m/z) Ex. Name Structure (M + H⁺) ¹H NMR  3 4-(((3S,4S)-1-((2-chloro-4- cyanophenyl)sulfonyl)- 4-hydroxy-4- (hydroxymethyl)pyrrolidin-3- yl)sulfonyl)-2- fluorobenzonitrile

500.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.36 (d, J = 1.5 Hz, 1H), 8.25 (dd, J= 8.3, 6.3 Hz, 1H), 8.10-8.14 (m, 1H), 8.00-8.07 (m, 2H), 7.88 (dd, J =8.2, 1.6 Hz, 1H), 5.79 (s, 1H), 5.21 (t, J = 5.8 Hz, 1H), 4.28 (t, J =8.3 Hz, 1H), 3.78-3.91 (m, 2H), 3.60 (dd, J = 11.3, 5.8 Hz, 1H), 3.54(d, J = 10.3 Hz, 1H), 3.42 (dd, J = 11.2, 5.6 Hz, 1H), 3.31-3.36 (1H,partially hidden by solvent peak)  4 4-(((3S,4S)-1- ((2-chlorophenyl)sulfonyl)-4-hydroxy- 4-(hydroxymethyl) pyrrolidin-3- yl)sulfonyl)-2-fluorobenzonitrile

474.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.24 (dd, J = 8.0, 6.3 Hz, 1H),7.95-8.05 (m, 2H), 7.87 (dd, J = 8.0, 1.5 Hz, 1H), 7.65-7.74 (m, 2H),7.52-7.58 (m, 1H), 5.74-5.77 (s, 1H), 5.19 (t, J = 5.6 Hz, 1H), 4.25 (t,J = 8.3 Hz, 1H), 3.75-3.86 (m, 2H), 3.58 (dd, J = 11.2, 5.6 Hz, 1H),3.50 (d, J = 10.0 Hz, 1H), 3.40 (dd, J = 11.3, 5.8 Hz, 1H), 3.30 (d, J =10.0 Hz, 1H)  5 4-(((3S,4S)-1- ((2-chloro-4- fluorophenyl)sulfonyl)-4-hydroxy- 4-(hydroxymethyl) pyrrolidin-3- yl)sulfonyl)-2-fluorobenzonitrile

492.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.24 (dd, J = 8.0, 6.3 Hz, 1H),7.99-8.07 (m, 2H), 7.88 (dd, J = 8.0, 1.5 Hz, 1H), 7.77 (dd, J = 8.8,2.8 Hz, 1H), 7.44 (m, 1H), 5.75 (s, 1H), 5.19 (t, J = 5.8 Hz, 1H), 4.24(t, J = 8.3 Hz, 1H), 3.73-3.87 (m, 2H), 3.58 (dd, J = 11.2, 5.6 Hz, 1H),3.50 (d, J = 10.0 Hz, 1H), 3.40 (dd, J = 11.2, 5.6 Hz, 1H), 3.29 (d, J =10.0 Hz, 1H)  6 4-(((3S,4S)-1- ((2-chloro-4- methylphenyl)sulfonyl)-4-hydroxy-4- (hydroxymethyl) pyrrolidin-3- yl)sulfonyl)-2-fluorobenzonitrile

488.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.24 (dd, J = 8.2, 6.4 Hz, 1H), 8.01(dd, J = 8.7, 1.4 Hz, 1H), 7.81-7.89 (m, 2H), 7.55 (s, 1H), 7.35 (d, J =7.3 Hz, 1H), 5.73 (s, 1H), 5.19 (t, J = 5.8 Hz, 1H), 4.22 (t, J = 8.3Hz, 1H), 3.71-3.83 (m, 2H), 3.57 (dd, J = 11.3, 5.8 Hz, 1H), 3.47 (d, J= 10.0 Hz, 1H), 3.38 (dd, J = 11.3, 5.8 Hz, 1H), 3.27 (d, J = 10.0 Hz,1H), 2.39 (s, 3H)  7 4-(((3S,4S)-1- ((2-chloro-4- (trifluoromethyl)phenyl)sulfonyl)- 4-hydroxy-4- (hydroxymethyl) pyrrolidin-3-yl)sulfonyl)-2- fluorobenzonitrile

542.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.24 (dd, J = 8.3, 6.3 Hz, 1H),8.14-8.20 (m, 2H), 8.02 (dd, J = 8.7, 1.4 Hz, 1H), 7.91-7.96 (m, 1H),7.88 (dd, J = 8.3, 1.5 Hz, 1H), 5.77 (s, 1H), 5.21 (t, J = 5.6 Hz, 1H),4.28 (t, J = 8.3 Hz, 1H), 3.79-3.92 (m, 2H), 3.61 (dd, J = 11.3, 5.8 Hz,1H), 3.55 (d, J = 10.3 Hz, 1H), 3.43 (dd, J = 11.2, 5.6 Hz, 1H), 3.36(m, 1H, partially hidden by solvent peak)  8 4-(((3S,4S)-1-((2-chloro-4- (trifluoromethoxy) phenyl)sulfonyl)- 4-hydroxy-4-(hydroxymethyl) pyrrolidin-3- yl)sulfonyl)-2- fluorobenzonitrile

558.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.24 (dd, J = 8.0, 6.3 Hz, 1H), 8.10(d, J = 8.8 Hz, 1H), 8.02 (dd, J = 8.7, 1.4 Hz, 1H), 7.84-7.90 (m, 2H),7.55-7.60 (m, 1H), 5.77 (s, 1H), 5.21 (t, J = 5.8 Hz, 1H), 4.26 (t, J =8.3 Hz, 1H), 3.77-3.87 (m, 2H), 3.60 (dd, J = 11.3, 5.8 Hz, 1H), 3.52(d, J = 10.3 Hz, 1H), 3.42 (dd, J = 11.2, 5.6 Hz, 1H), 3.32 (d, J = 10.0Hz, 1H, partially hidden by solvent peak)  9 4-(((3S,4S)-1-((2,4-dichloro-5- fluorophenyl)sulfonyl)- 4-hydroxy-4- (hydroxymethyl)pyrrolidin-3- yl)sulfonyl)-2- fluorobenzonitrile

526.7 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.24 (dd, J = 8.0, 6.3 Hz, 1H), 8.14(d, J = 6.3 Hz, 1H), 8.02 (dd, J = 8.7, 1.4 Hz, 1H), 7.97 (d, J = 8.8Hz, 1H), 7.88 (dd, J = 8.3, 1.5 Hz, 1H), 5.79 (s, 1H), 5.22 (t, J = 5.5Hz, 1H), 4.27 (t, J = 8.3 Hz, 1H), 3.79-3.90 (m, 2H), 3.61 (dd, J =11.2, 5.4 Hz, 1H), 3.54 (d, J = 10.3 Hz, 1H), 3.43 (dd, J = 11.2, 5.4Hz, 1H), 3.32-3.37 (1H, partially hidden by solvent peak) 104-(((3S,4R)-1- ((2-chloro-4- cyanophenyl)sulfonyl)- 4-hydroxy-4-(hydroxymethyl) pyrrolidin-3- yl)sulfonyl)-2- fluorobenzonitrile

500.1 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.38 (d, J = 1.5 Hz, 1H), 8.29 (dd, J= 8.2, 6.1 Hz, 1H), 8.10-8.15 (m, 1H), 8.04-8.09 (m, 2H), 7.86 (dd, J =8.2, 1.6 Hz, 1H), 5.87 (s, 1H), 4.99 (t, J = 5.3 Hz, 1H), 4.33 (dd, J =7.4, 3.4 Hz, 1H), 3.84 (dd, J = 11.8, 7.5 Hz, 1H), 3.60- 3.75 (m, 4H),3.38 (d, J = 10.0 Hz, 1H) 11 4-(((3S,4R)-1- ((2-chloro-phenyl)sulfonyl)- 4-hydroxy-4- (hydroxymethyl) pyrrolidin-3-yl)sulfonyl)-2- fluorobenzonitrile

474.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.27 (dd, J = 8.0, 6.3 Hz, 1H), 8.04(dd, J = 8.5, 1.5 Hz, 1H), 7.98 (dd, J = 7.9, 1.4 Hz, 1H), 7.82 (dd, J =8.2, 1.6 Hz, 1H), 7.67-7.77 (m, 2H), 7.54-7.60 (m, 1H), 5.83 (s, 1H),4.97 (t, J = 5.4 Hz, 1H), 4.31 (dd, J = 7.5, 3.5 Hz, 1H), 3.79 (dd, J =11.5, 7.5 Hz, 1H), 3.61-3.74 (m, 3H), 3.58 (dd, J = 11.5, 3.5 Hz, 1H),3.33-3.37 (1H, partially hidden by solvent peak) 12 4-(((3S,4R)-1-((2-chloro-4- fluorophenyl)sulfonyl)- 4-hydroxy-4- (hydroxymethyl)pyrrolidin-3- yl)sulfonyl)-2- fluorobenzonitrile

492.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.28 (dd, J = 8.0, 6.3 Hz, 1H),8.01-8.07 (m, 2H), 7.86 (dd, J = 8.0, 1.5 Hz, 1H), 7.80 (dd, J = 8.8,2.5 Hz, 1H), 7.43-7.50 (m, 1H), 5.82 (s, 1H), 4.97 (t, J = 5.4 Hz, 1H),4.31 (dd, J = 7.7, 3.6 Hz, 1H), 3.79 (dd, J = 11.5, 7.5 Hz, 1H),3.56-3.74 (m, 4H), 3.31-3.36 (1H, partially hidden by solvent peak) 134-(((3S,4R)-1- ((2-chloro-4- methylphenyl)sulfonyl)- 4-hydroxy-4-(hydroxymethyl) pyrrolidin-3- yl)sulfonyl)-2- fluorobenzonitrile

488.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.27 (dd, J = 8.0, 6.3 Hz, 1H), 8.02(dd, J = 8.5, 1.5 Hz, 1H), 7.80-7.88 (m, 2H), 7.58 (d, J = 0.8 Hz, 1H),7.37 (dd, J = 8.0, 0.8 Hz, 1H), 5.79 (s, 1H), 4.96 (t, J = 5.4 Hz, 1H),4.29 (dd, J = 7.5, 3.8 Hz, 1H), 3.61-3.80 (m, 4H), 3.55 (dd, J = 11.5,3.8 Hz, 1H), 3.31 (d, J = 9.8 Hz, 1H), 2.41 (s, 3H) 14 4-(((3S,4R)-1-((2-chloro-4- (trifluoromethyl) phenyl)sulfonyl)- 4-hydroxy-4-(hydroxymethyl) pyrrolidin-3- yl)sulfonyl)-2- fluorobenzonitrile

542.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.28 (dd, J = 8.3, 6.3 Hz, 1H),8.16-8.22 (m, 2H), 8.03 (dd, J = 8.5, 1.5 Hz, 1H), 7.96 (dd, J = 8.3,1.0 Hz, 1H), 7.86 (dd, J = 8.2, 1.6 Hz, 1H), 5.86 (s, 1H), 4.99 (t, J =5.3 Hz, 1H), 4.33 (dd, J = 7.5, 3.5 Hz, 1H), 3.84 (dd, J = 11.7, 7.7 Hz,1H), 3.68-3.75 (m, 2H), 3.60-3.67 (m, 2H), 3.39 (d, J = 9.8 Hz, 1H) 154-(((3S,4R)-1- ((2-chloro-4- (trifluoromethoxy) phenyl)sulfonyl)-4-hydroxy-4- (hydroxymethyl) pyrrolidin-3- yl)sulfonyl)-2-fluorobenzonitrile

559.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.28 (dd, J = 8.3, 6.3 Hz, 1H), 8.11(d, J = 8.8 Hz, 1H), 8.04 (dd, J = 8.5, 1.5 Hz, 1H), 7.83-7.90 (m, 2H),7.58-7.64 (m, 1H), 5.85 (s, 1H), 4.99 (t, J = 5.4 Hz, 1H), 4.32 (dd, J =7.5, 3.3 Hz, 1H), 3.81 (dd, J = 11.5, 7.5 Hz, 1H), 3.56-3.75 (m, 4H),3.37 (d, J = 9.8 Hz, 1H, partially hidden by solvent peak) 164-(((3S,4R)-1- ((2,4-dichloro-5- fluorophenyl)sulfonyl)- 4-hydroxy-4-(hydroxymethyl) pyrrolidin-3- yl)sulfonyl)-2- fluorobenzonitrile

527.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.28 (dd, J = 8.0, 6.3 Hz, 1H), 8.17(d, J = 6.5 Hz, 1H), 8.06 (dd, J = 8.7, 1.4 Hz, 1H), 8.00 (d, J = 8.8Hz, 1H), 7.90 (dd, J = 8.2, 1.6 Hz, 1H), 5.87 (s, 1H), 4.99 (t, J = 5.3Hz, 1H), 4.34 (dd, J = 7.5, 3.3 Hz, 1H), 3.85 (dd, J = 11.8, 7.5 Hz,1H), 3.60-3.74 (m, 4H), 3.39 (d, J = 10.0 Hz, 1H) 17 5-chloro-2-(((3R,4S)-4-((4- chlorophenyl)sulfonyl)- 3-hydroxy-3- (hydroxymethyl)pyrrolidin-1- yl)sulfonyl)benzonitrile

491.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.42 (s, 1H), 8.00-8.08 (m, 2H),7.74-7.84 (m, 4H), 5.70 (s, 1H), 4.95 (t, J = 5.3 Hz, 1H), 4.12 (dd, J =7.5, 3.3 Hz, 1H), 3.66-3.77 (m, 2H), 3.57-3.64 (m, 2H), 3.53 (dd, J =11.5, 3.0 Hz, 1H), 3.34- 3.39 (m, 1H) 18 (3R,4S)-4-((4-chlorophenyl)sulfonyl)- 1-((2,4-dichloro- phenyl)sulfonyl)-3-(hydroxymethyl) pyrrolidin-3-ol

500.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 7.93-8.00 (m, 2H), 7.81-7.86 (m, 2H),7.73-7.78 (m, 2H), 7.67 (dd, J = 8.5, 2.0 Hz, 1H), 5.70 (s, 1H), 4.93(t, J = 5.4 Hz, 1H), 4.13 (dd, J = 7.5, 3.5 Hz, 1H), 3.71-3.81 (m, 2H),3.66 (d, J = 9.0 Hz, 2H), 3.54 (dd, J = 11.3, 3.5 Hz, 1H), 3.31-3.36(1H, partially hidden solvent peak) 19 4-(((3R,4S)-4- ((4-chloro-phenyl)sulfonyl)- 3-hydroxy-3- (hydroxymethyl) pyrrolidin-1-yl)sulfonyl)-3- (trifluoromethyl) benzonitrile

524.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.59 (s, 1H), 8.43 (d, J = 8.3 Hz,1H), 8.28 (d, J = 8.3 Hz, 1H), 7.84-7.90 (m, 2H), 7.77 (d, J = 8.5 Hz,2H), 5.85 (s, 1H), 4.99 (t, J = 5.4 Hz, 1H), 4.14-4.18 (m, 1H),3.74-3.83 (m, 2H), 3.67 (d, J = 10.0 Hz, 2H), 3.58 (dd, J = 11.4, 2.9Hz, 1H), 3.41 (d, J = 9.8 Hz, 1H) 20 4-(((3R,4S)-4- ((4-chloro-phenyl)sulfonyl)- 3-hydroxy-3- (hydroxymethyl) pyrrolidin-1-yl)sulfonyl)-3- methylbenzonitrile

471.3 ¹H NMR (400 MHz, DMSO-d₆) δ: 7.97-8.05 (m, 2H), 7.90-7.95 (m, 1H),7.81-7.87 (m, 2H), 7.73-7.78 (m, 2H), 5.76 (s, 1H), 4.95 (t, J = 5.4 Hz,1H), 4.11-4.16 (m, 1H), 3.57-3.80 (m, 4H), 3.45 (dd, J = 11.3, 3.0 Hz,1H), 3.30-3.34 (H, partially hidden by solvent peak), 2.61 (s, 3H) 214-(((3R,4S)-4- ((4-chloro- phenyl)sulfonyl)- 3-hydroxy-3-(hydroxymethyl) pyrrolidin-1- yl)sulfonyl)-3- fluorobenzonitrile

475.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.23 (d, J = 10.0 Hz, 1H), 7.92- 8.02(m, 2H), 7.74-7.81 (m, 4H), 5.70 (s, 1H), 4.93 (t, J = 5.1 Hz, 1H),4.08-4.13 (m, 1H), 3.69-3.77 (m, 2H), 3.55-3.63 (m, 2H), 3.48 (dd, J =11.5, 2.5 Hz, 1H), 3.36 (d, J = 10.0 Hz, 1H)

Example 224-(((3S,4R)-1-((2-bromo-4-fluorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile

Step 1: (R)-tert-butyl3-((4-cyanophenyl)thio)-4-methylenepyrrolidine-1-carboxylate

A 3-neck flask, equipped with a mechanical stirrer and thermocouple, wascharged with a solution of (S)-tert-butyl3-methylene-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (28.8 g,104 mmol) in DMF (300 mL). 4-mercaptobenzonitrile (16.9 g, 125 mmol) wasadded followed by K₂CO₃ (21.5 g, 156 mmol) and the reaction mixture wasstirred at rt for 1 h. Additional DMF (100 mL) was added to facilitatestirring and two additional portions of 4-mercaptobenzonitrile (4.2 g,31 mmoL each) were added 30 min apart. The reaction was quenched withH₂O (500 mL) and extracted with hexanes/EtOAc (1:1, 2×500 mL). Thecombined extracts were washed with H₂O (4×500 mL), brine (1×500 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude product was purified by flash column chromatography (SiO₂) elutingwith a gradient of 0-60% EtOAc in hexanes. The product fractions werepooled, concentrated and triturated with DCM/hexane (100 mL/300 mL). Thesolid was removed by filtration, washed with hexanes (3×100 mL) anddiscarded. The filtrate was concentrated under reduced pressure to givethe title compound as a yellow oil (19.7 g, 60% yield). MS (m/z) 251.2(M+H⁺-Boc).

Step 2: (3R,4S)-tert-butyl4-((4-cyanophenyl)thio)-3-hydroxy-3-(hydroxymethyl)pyrrolidine-1-carboxylateand (3S,4S)-tert-butyl4-((4-cyanophenyl)thio)-3-hydroxy-3-(hydroxymethyl)pyrrolidine-1-carboxylate

To a solution of (R)-tert-butyl3-((4-cyanophenyl)thio)-4-methylenepyrrolidine-1-carboxylate (19.6 g,61.8 mmol) in THE (300 mL) was added NMO (50% in water) (29.0 g, 124mmol) followed by OsO₄ (2.5% in t-BuOH) (38.8 mL, 3.09 mmol) and themixture was stirred at rt. After 2.5 h, the mixture was diluted with DCMand stirred with 10% Na₂S₂O₃ (aq) for 72 h. The organic layer wasremoved and washed with 10% NaHCO₃ (aq), water, brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure to give thetitle compound as a sticky, beige foam (24.6 g 114% yield). MS (m/z)251.2 (M+H⁺-Boc). This material was used as is in the next step.

Step 3: (3R,4S)-tert-butyl4-((4-cyanophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidine-1-carboxylateand (3S,4S)-tert-butyl4-((4-cyanophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidine-1-carboxylate

A mixture of (3R,4S)-tert-butyl4-((4-cyanophenyl)thio)-3-hydroxy-3-(hydroxymethyl)pyrrolidine-1-carboxylateand (3S,4S)-tert-butyl4-((4-cyanophenyl)thio)-3-hydroxy-3-(hydroxymethyl)pyrrolidine-1-carboxylate(26.4 g, 75 mmol) was dissolved in DCM (500 mL), treated with m-CPBA(67.5 g, 300 mmol) added portionwise and stirred at rt for 18 h. Thereaction was quenched with 10% Na₂S₂O₃ (aq) (500 mL), and the resultingsuspension filtered to remove a non-product solid. The biphasic filtratewas transferred to a separatory funnel, the aqueous layer removed andthe DCM layer washed with 10% NaHCO₃ (aq). The DCM layer was collectedand the basic aqueous phase was extracted a second time with DCM (200mL). The organic extracts were combined, washed with H₂O, dried overNa₂SO₄, filtered and concentrated under reduced pressure to afford thetitle compound as a white foam (21.6 g, 75% yield). This samplecontained an estimated 80/20 mixture of trans/cis isomers (by LCMS) andwas used as is in the next step. MS (m/z) 405.0 (M+Na⁺).

Step 4: (5R,9S)-tert-butyl9-((4-cyanophenyl)sulfonyl)-2,2-dimethyl-1,3-dioxa-7-azaspiro[4.4]nonane-7-carboxylateor (5S,9S)-tert-butyl9-((4-cyanophenyl)sulfonyl)-2,2-dimethyl-1,3-dioxa-7-azaspiro[4.4]nonane-7-carboxylate

To a suspension of (3R,4S)-tert-butyl4-((4-cyanophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidine-1-carboxylateand (3S,4S)-tert-butyl4-((4-cyanophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidine-1-carboxylate(21.7 g, 56.7 mmol) in 2,2-dimethoxypropane (70 mL, 570 mmol) was addedp-toluenesulfonic acid monohydrate (2.2 g, 11.3 mmol) and the mixturewas stirred at rt for 1.5 h. The reaction mixture was diluted with DCMand quenched with sat'd NaHCO₃ (aq). The water layer was removed and theDCM layer was washed with H₂O, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude isomer mixture waspurified and separated by flash column chromatography (SiO₂) elutingwith a gradient of 0-50% EtOAc in hexanes to give the title compounds asthe individual trans and cis isomers. Trans-isomer: 1^(st) elutant,white foam (13.5 g, 56.4% yield), ¹H NMR (400 MHz, DMSO-d₆) δ: 8.22 (d,J=5.8 Hz, 2H), 8.11-8.20 (m, 2H), 4.51-4.61 (m, 1H), 4.36 (d, J=7.0 Hz,1H), 4.13 (d, J=9.8 Hz, 1H), 3.46-3.59 (m, 3H), 3.32-3.38 (m, 1H,partially hidden by solvent peak), 1.28-1.45 (m, 15H), MS (m/z) 323.2(M+H⁺-Boc). Cis-isomer: 2^(nd) eluant, white solid (4.31 g, 18% yield),¹H NMR (400 MHz, DMSO-d₆) δ: 8.14-8.22 (m, 2H), 8.05-8.13 (m, 2H), 4.41(br s, 1H), 3.91-4.08 (m, 3H), 3.43-3.67 (m, 2H), 3.32-3.40 (m, 1H,partially hidden by solvent peak), 1.42 (d, J=4.8 Hz, 9H), 1.17-1.26 (m,3H), 0.68 (d, J=8.0 Hz, 3H), MS (m/z) 445.2 (M+Na⁺).

Step 5:4-(((3S,4R)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile,Hydrochloride

A solution of (5R,9S)-tert-butyl9-((4-cyanophenyl)sulfonyl)-2,2-dimethyl-1,3-dioxa-7-azaspiro[4.4]nonane-7-carboxylate(13.5 g, 32.0 mmol) in DCM (70 mL), at rt, was treated with TFA (150 mL,1.95 mol) followed by H₂O (1.15 mL, 63.9 mmol) and stirred for 1 h. Themixture was concentrated under reduced pressure and the residueazeotroped with CHCl₃ (3×300 mL). The residue was dissolved in MeOH, 1 NHCl in Et₂O (200 mL) was added and concentrated. The residue was treatedwith a second portion of 1 N HCl in Et₂O (200 mL) and concentrated. Theresidue was redissolved and reconcentrated from Et₂O (3×, 150 mL each),dried under reduced pressure to afford the title compound as a lightbeige solid (12.6 g, 126% yield). MS (m/z) 283.1 (M+H⁺).

Step 6:4-(((3S,4R)-1-((2-bromo-4-fluorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile

To a suspension of4-(((3S,4R)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile,Hydrochloride (100 mg, 0.317 mmol) in THE (2.5 mL), was added 10% NaHCO₃(aq) (2.5 mL), followed by 2-bromo-4-fluorobenzene-1-sulfonyl chloride(95 mg, 0.347 mmol) and the mixture was stirred for 30 min. The reactionmixture was diluted with EtOAc, washed with H₂O and brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The cruderesidue was purified by flash column chromatography (SiO₂) eluting with0-60% EtOAc/EtOH (3:1) in hexanes. The product fractions were pooled andconcentrated under reduced pressure to give a white solid (84 mg). Thesample was further purified by reverse-phase semi-prep HPLC, elutingwith a gradient of 10-95% CH₃CN/H₂O (0.1% TFA). The pure fractions werepooled, diluted with EtOAc and the aqueous phase separated. The organicphase was washed with 10% NaHCO₃ (aq), H₂O and brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the titlecompound as a white foam (52 mg, 32% yield). ¹H NMR (400 MHz, DMSO-d₆)δ: 8.18 (d, J=8.0 Hz, 2H), 8.01-8.10 (m, 3H), 7.93 (d, J=7.8 Hz, 1H),7.50 (t, J=7.8 Hz, 1H), 5.79 (s, 1H), 4.99 (br s, 1H), 4.25 (d, J=3.3Hz, 1H), 3.54-3.83 (m, 5H), 3.30-3.36 (1H, partially hidden by solventpeak). MS (m/z) 519.0 (M+H⁺).

The following compounds were prepared using procedures analogous tothose described in Example 22 using appropriately substituted startingmaterials. As is appreciated by those skilled in the art, theseanalogous examples may involve variations in general reactionconditions.

MS (m/z) Ex. Name Structure (M + H⁺) ¹H NMR 23 3-chloro-4-(((3S,4S)-4-((4- chlorophenyl)sulfonyl)- 3-hydroxy-3- (hydroxymethyl)pyrrolidin-1- yl)sulfonyl)benzonitrile

491.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.33 (s, 1H), 8.08-8.13 (m, 1H),8.00-8.04 (m, 1H), 7.86 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 8.5 Hz, 2H),5.65 (s, 1H), 5.14 (t, J = 5.5 Hz, 1H), 4.12 (t, J = 8.5 Hz, 1H),3.74-3.86 (m, 2H), 3.50-3.61 (m, 2H), 3.42 (dd, J = 11.2, 5.4 Hz, 1H),3.29-3.34 (1H, partially hidden by solvent peak) 24 4-(((3S,4S)-4-((4-bromo- phenyl)sulfonyl)- 3-hydroxy-3- (hydroxymethyl) pyrrolidin-1-yl)sulfonyl)-3- chlorobenzonitrile

557.4 M + Na ¹H NMR (400 MHz, DMSO-d₆) δ: 8.33 (s, 1H), 8.11 (d, J = 8.0Hz, 1H), 8.00-8.05 (m, 1H), 7.86 (d, J = 7.8 Hz, 2H), 7.75-7.81 (m, 2H),5.66 (s, 1H), 5.13-5.18 (m, 1H), 4.12 (t, J = 8.4 Hz, 1H), 3.73-3.86 (m,2H), 3.50-3.63 (m, 2H), 3.42 (dd, J = 11.0, 5.0 Hz, 1H), 3.30- 3.34 (1H,hidden under solvent peak) 25 4-(((3S,4R)-1- ((4-chloro-2-(trifluoromethyl) phenyl)sulfonyl)- 4-hydroxy-4- (hydroxymethyl)pyrrolidin-3- yl)sulfonyl)benzo- nitrile

524.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.18 (d, J = 8.5 Hz, 2H), 8.10- 8.15(m, 2H), 8.00-8.08 (m, 3H), 5.87 (s, 1H), 5.01 (t, J = 5.4 Hz, 1H), 4.26(dd, J = 7.5, 3.3 Hz, 1H), 3.71-3.77 (m, 2H), 3.61-3.67 (m, 2H), 3.57(dd, J = 11.5, 3.3 Hz, 1H), 3.34-3.39 (1H, partially hidden by solventpeak) 26 3-chloro-4- (((3R,4S)-3- hydroxy-3- (hydroxymethyl)- 4-((6-(trifluoromethyl) pyridin-3- yl)sulfonyl)pyrrolidin- 1-yl)sulfonyl)benzonitrile

525.9 ¹H NMR (400 MHz, DMSO-d₆) δ: 9.22 (s, 1H), 8.56 (d, J = 8.0 Hz,1H), 8.37 (s, 1H), 8.24 (d, J = 8.3 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H),8.04-8.10 (m, 1H), 5.81 (br s, 1H), 4.95 (br s, 1H), 4.37 (dd, J = 7.2,3.9 Hz, 1H), 3.89 (dd, J = 11.2, 7.4 Hz, 1H), 3.63-3.81 (m, 4H), 3.36(d, J = 10.0 Hz, 1H, partially hidden by solvent peak) 27 4-(((3R,4S)-3-hydroxy-3- (hydroxymethyl)- 4-((6- (trifluoromethyl) pyridin-3-yl)sulfonyl)pyrrolidin- 1-yl)sulfonyl)-3- (trifluoromethyl) benzonitrile

559.9 ¹H NMR (400 MHz, DMSO-d₆) δ: 9.23 (s, 1H), 8.55-8.62 (m, 2H), 8.44(d, J = 8.0 Hz, 1H), 8.30 (d, J = 8.3 Hz, 1H), 8.25 (d, J = 8.3 Hz, 1H),5.91 (s, 1H), 4.99 (t, J = 5.3 Hz, 1H), 4.39 (dd, J = 7.2, 3.4 Hz, 1H),3.82-3.89 (m, 1H), 3.64- 3.79 (m, 4H), 3.39 (d, J = 10.0 Hz, 1H) 284-(((3S,4R)-4- hydroxy-4- (hydroxymethyl)- 1-((2-methyl-4-(trifluoromethyl) phenyl)sulfonyl) pyrrolidin-3-yl)sulfonyl)benzonitrile

505.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.16 (d, J = 8.8 Hz, 2H), 7.98- 8.07(m, 3H), 7.92 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 5.82 (s, 1H), 4.99 (t,J = 5.5 Hz, 1H), 4.25 (dd, J = 7.5, 3.3 Hz, 1H), 3.58-3.78 (m, 4H), 3.46(dd, J = 11.3, 3.5 Hz, 1H), 3.32 (d, J = 9.8 Hz, 1H, partially hidden bysolvent peak), 2.66 (s, 3H) 29 4-(((3S,4R)-1- ((4-fluoro-2-(trifluoromethyl) phenyl)sulfonyl)- 4-hydroxy-4- (hydroxymethyl)pyrrolidin-3- yl)sulfonyl)benzonitrile

509.1 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.16-8.23 (m, 3H), 8.04 (d, J = 8.3Hz, 2H), 7.99 (dd, J = 9.3, 2.5 Hz, 1H), 7.78-7.85 (m, 1H), 5.87 (s,1H), 5.01 (br s, 1H), 4.26 (dd, J = 7.3, 3.3 Hz, 1H), 3.70-3.77 (m, 2H),3.64 (d, J = 10.0 Hz, 2H), 3.56 (dd, J = 11.5, 3.3 Hz, 1H), 3.33-3.39(1H, partially hidden by solvent peak) 30 4-(((3S,4R)-1- ((4-bromo-2-(trifluoromethyl) phenyl)sulfonyl)- 4-hydroxy-4- (hydroxymethyl)pyrrolidin-3- yl)sulfonyl)benzonitrile

568.6 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.15-8.25 (m, 4H), 8.01-8.07 (m, 3H),5.87 (s, 1H), 5.01 (br s, 1H), 4.26 (dd, J = 7.3, 3.3 Hz, 1H), 3.70-3.79(m, 2H), 3.64 (d, J = 10.0 Hz, 2H), 3.56 (dd, J = 11.4, 3.4 Hz, 1H),3.35 (d, J = 9.5 Hz, 1H, partially hidden by solvent peak) 314-(((3S,4R)-4- hydroxy-4- (hydroxymethyl)- 1-((4-methoxy-2-(trifluoromethyl) phenyl)sulfonyl) pyrrolidin-3-yl)sulfonyl)benzonitrile

520.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.18 (d, J = 8.3 Hz, 2H), 7.98- 8.10(m, 3H), 7.39-7.51 (m, 2H), 5.80 (s, 1H), 4.99 (t, J = 4.9 Hz, 1H), 4.24(dd, J = 7.5, 3.5 Hz, 1H), 3.95 (s, 3H), 3.57-3.76 (m, 4H), 3.50 (dd, J= 11.3, 3.5 Hz, 1H), 3.31 (d, J = 9.8 Hz, 1H) 32 4-(((3S,4R)-1-((2-bromo-4- (trifluoromethyl) phenyl)sulfonyl)- 4-hydroxy-4-(hydroxymethyl) pyrrolidin-3- yl)sulfonyl)benzonitrile

569.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.32 (s, 1H), 8.14-8.25 (m, 3H),7.97-8.10 (m, 3H), 5.82 (s, 1H), 5.00 (br s, 1H), 4.27 (dd, J = 7.4, 3.6Hz, 1H), 3.84 (dd, J = 11.4, 7.7 Hz, 1H), 3.58-3.79 (m, 4H), 3.38 (d, J= 10.0 Hz, 1H, partially hidden by solvent peak) 33 4-(((3S,4R)-1-((2-bromo- phenyl)sulfonyl)- 4-hydroxy-4- (hydroxymethyl) pyrrolidin-3-yl)sulfonyl)benzonitrile

500.7 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.17 (d, J = 8.3 Hz, 2H), 7.97- 8.04(m, 3H), 7.89-7.94 (m, 1H), 7.56-7.66 (m, 2H), 5.78 (s, 1H), 4.98 (t, J= 5.3 Hz, 1H), 4.25 (dd, J = 7.5, 3.8 Hz, 1H), 3.63-3.82 (m, 4H), 3.56(dd, J = 11.3, 3.8 Hz, 1H), 3.31-3.37 (1H, partially hidden by solventpeak) 34 4-(((3S,4R)-1- ((4-bromo-2- chlorophenyl)sulfonyl)-4-hydroxy-4- (hydroxymethyl) pyrrolidin-3- yl)sulfonyl)benzonitrile

535.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.17 (d, J = 8.8 Hz, 2H), 8.07 (d, J= 1.8 Hz, 1H), 8.02 (d, J = 8.8 Hz, 2H), 7.86-7.90 (m, 1H), 7.78- 7.82(m, 1H), 5.76-5.79 (m, 1H), 4.97 (t, J = 5.4 Hz, 1H), 4.24 (dd, J = 7.7,3.6 Hz, 1H), 3.69-3.81 (m, 2H), 3.61-3.68 (m, 2H), 3.56 (dd, J = 11.4,3.6 Hz, 1H), 3.32 (d, J = 10.0 Hz, 1H, partially hidden by solvent peak)35 4-(((3R,4S)-4- ((4-chloro- phenyl)sulfonyl)- 3-hydroxy-3-(hydroxymethyl) pyrrolidin-1- yl)sulfonyl)-3- methoxybenzonitrile

486.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 7.88 (d, J = 8.0 Hz, 1H), 7.82 (d, J= 1.3 Hz, 1H), 7.73-7.80 (m, 4H), 7.58 (dd, J = 8.0, 1.5 Hz, 1H), 5.62(s, 1H), 4.91 (t, J = 5.5 Hz, 1H), 4.07 (dd, J = 7.9, 4.1 Hz, 1H), 3.91(s, 3H), 3.76 (dd, J = 11.4, 7.9 Hz, 1H), 3.58-3.70 (m, 3H), 3.54 (dd, J= 11.3, 4.3 Hz, 1H), 3.22 (d, J = 9.8 Hz, 1H) 36 4-(((3S,4R)-1-((2-fluoro-4- (trifluoromethyl) phenyl)sulfonyl)- 4-hydroxy-4-(hydroxymethyl) pyrrolidin-3- yl)sulfonyl)benzonitrile

508.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.17 (d, J = 8.5 Hz, 2H), 8.10 (d, J= 9.3 Hz, 1H), 8.03 (t, J = 7.4 Hz, 1H), 7.94-7.98 (m, 2H), 7.85 (dd, J= 8.3, 1.0 Hz, 1H), 5.77 (s, 1H), 4.98 (br s, 1H), 4.22 (dd, J = 7.4,2.9 Hz, 1H), 3.67-3.79 (m, 2H), 3.57-3.63 (m, 2H), 3.50 (dd, J = 11.8,3.0 Hz, 1H), 3.37 (d, J = 10.0 Hz, 1H, partially hidden by solvent peak)37 (3R,4S)-1-((2- chloro-4- (difluoromethyl) phenyl)sulfonyl)-4-((4-chloro- phenyl)sulfonyl)-3- (hydroxymethyl) pyrrolidin-3-ol

516.1 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.12 (d, J = 8.0 Hz, 1H), 7.94 (s,1H), 7.71-7.84 (m, 5H), 7.00-7.32 (m, 1H), 5.71 (s, 1H), 4.93 (t, J =5.4 Hz, 1H), 4.13 (dd, J = 7.5, 3.3 Hz, 1H), 3.74-3.82 (m, 2H), 3.65-3.73 (m, 2H), 3.54 (dd, J = 11.3, 3.3 Hz, 1H), 3.38 (d, J = 9.8 Hz, 1H)38 3-bromo-4- (((3R,4S)-4-((4- chlorophenyl)sulfonyl)- 3-hydroxy-3-(hydroxymethyl) pyrrolidin-1- yl)sulfonyl)benzonitrile

534.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.51 (s, 1H), 8.08-8.16 (m, 2H),7.83-7.89 (m, 2H), 7.74-7.80 (m, 2H), 5.79 (s, 1H), 4.99 (t, J = 5.5 Hz,1H), 4.16 (dd, J = 7.4, 3.4 Hz, 1H), 3.73-3.87 (m, 2H), 3.63-3.72 (m,2H), 3.60 (dd, J = 11.4, 3.4 Hz, 1H), 3.35-3.40 (1H, partially hidden bysolvent peak) 39 3-bromo-4- (((3R,4S)-3- hydroxy-3- (hydroxymethyl)-4-((6- (trifluoromethyl) pyridin-3- yl)sulfonyl)pyrrolidin-1-yl)sulfonyl) benzonitrile

570.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 9.23 (s, 1H), 8.58 (d, J = 8.0 Hz,1H), 8.50 (s, 1H), 8.24 (d, J = 8.3 Hz, 1H), 8.07-8.19 (m, 2H), 5.81 (s,1H), 4.93-4.99 (m, 1H), 4.40 (d, J = 4.0 Hz, 1H), 3.86-3.94 (m, 1H),3.65-3.82 (m, 4H), 3.36 (d, J = 9.8 Hz, 1H) 40 5-chloro-2- (((3R,4S)-3-hydroxy-3- (hydroxymethyl)- 4-((6- (trifluoromethyl) pyridin-3-yl)sulfonyl)pyrrolidin- 1-yl)sulfonyl) benzonitrile

525.9 ¹H NMR (400 MHz, DMSO-d₆) δ: 9.20 (s, 1H), 8.55 (d, J = 8.0 Hz,1H), 8.41 (s, 1H), 8.24 (d, J = 8.3 Hz, 1H), 8.05 (s, 2H), 5.75 (s, 1H),4.93 (t, J = 5.3 Hz, 1H), 4.35 (dd, J = 7.3, 3.8 Hz, 1H), 3.79- 3.88 (m,1H), 3.70-3.77 (m, 1H), 3.58-3.68 (m, 3H), 3.33 (d, J = 10.3 Hz, 1H,partially hidden by solvent peak) 41 4-(((3S,4R)-4- hydroxy-4-(hydroxymethyl)- 1-((2- (trifluoromethyl) phenyl)sulfonyl) pyrrolidin-3-yl)sulfonyl)benzonitrile

491.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.18 (d, J = 8.5 Hz, 2H), 8.09- 8.14(m, 1H), 8.00-8.07 (m, 3H), 7.88-7.97 (m, 2H), 5.88 (s, 1H), 5.01 (br s,1H), 4.26 (dd, J = 7.4, 3.4 Hz, 1H), 3.71-3.79 (m, 2H), 3.62-3.70 (m,2H), 3.55 (dd, J = 11.5, 3.3 Hz, 1H), 3.38 (d, J = 10.0 Hz, 1H,partially hidden by solvent peak) 42 4-(((3S,4R)-1- ((2-chloro-4-(difluoromethyl) phenyl)sulfonyl)- 4-hydroxy-4- (hydroxymethyl)pyrrolidin-3- yl)sulfonyl)benzonitrile

507.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.14-8.20 (m, 2H), 8.12 (d, J = 8.3Hz, 1H), 7.98-8.03 (m, 2H), 7.95 (s, 1H), 7.78 (d, J = 8.3 Hz, 1H),7.02-7.33 (m, 1H), 5.80 (s, 1H), 4.99 (t, J = 5.4 Hz, 1H), 4.25 (dd, J =7.5, 3.5 Hz, 1H), 3.62- 3.84 (m, 4H), 3.56 (dd, J = 11.5, 3.5 Hz, 1H),3.37 (d, J = 9.8 Hz, 1H) 43 (3R,4S)-1-((2- chloro-4- (fluoromethyl)phenyl)sulfonyl)-4- ((4-chloro- phenyl)sulfonyl)-3- (hydroxymethyl)pyrrolidin-3-ol

498.2 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.02 (d, J = 8.3 Hz, 1H), 7.78- 7.83(m, 2H), 7.72-7.77 (m, 3H), 7.59 (d, J = 8.0 Hz, 1H), 5.69 (s, 1H), 5.63(s, 1H), 5.51 (s, 1H), 4.92 (t, J = 5.3 Hz, 1H), 4.12 (dd, J = 7.3, 3.5Hz, 1H), 3.73-3.80 (m, 2H), 3.65-3.72 (m, 2H), 3.52 (dd, J = 11.3, 3.5Hz, 1H), 3.35 (d, J = 9.8 Hz, 1H) 44 4-(((3S,4R)-1- ((2-chloro-4-(fluoromethyl) phenyl)sulfonyl)-4- hydroxy-4- (hydroxymethyl)pyrrolidin-3- yl)sulfonyl)benzonitrile

489.1 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.16 (d, J = 8.3 Hz, 2H), 7.96- 8.04(m, 3H), 7.75 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 5.73 (s, 1H), 5.63 (s,1H), 5.52 (s, 1H), 4.93 (t, J = 5.3 Hz, 1H), 4.20-4.25 (m, 1H),3.63-3.82 (m, 4H), 3.55 (dd, J = 11.2, 3.4 Hz, 1H), 3.35 (d, J = 9.8 Hz,1H, partially hidden by solvent peak) 45 3-chloro-4- (((3R,4S)-4-((4-cyanophenyl)sulfonyl)- 3-hydroxy-3- (hydroxymethyl) pyrrolidin-1-yl)sulfonyl)benzonitrile

482.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.38 (d, J = 1.3 Hz, 1H), 8.16- 8.21(m, 2H), 8.11-8.15 (m, 1H), 8.05-8.09 (m, 1H), 8.03 (d, J = 8.8 Hz, 2H),5.84 (s, 1H), 5.00 (t, J = 5.4 Hz, 1H), 4.26 (dd, J = 7.5, 3.5 Hz, 1H),3.82 (dd, J = 11.5, 7.5 Hz, 1H), 3.58-3.76 (m, 4H), 3.37 (d, J = 10.0Hz, 1H) 46 4-(((3R,4S)-4- ((4-chloro- phenyl)sulfonyl)- 3-hydroxy-3-(hydroxymethyl) pyrrolidin-1- yl)sulfonyl)-3- ethylbenzonitrile

485.3 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.05 (s, 1H), 7.96-8.01 (m, 1H),7.89-7.93 (m, 1H), 7.82-7.87 (m, 2H), 7.74-7.79 (m, 2H), 5.77 (s, 1H),4.95 (br s, 1H), 4.14 (d, J = 4.3 Hz, 1H), 3.58-3.80 (m, 4H), 3.47 (dd,J = 11.3, 2.8 Hz, 1H), 3.31-3.37 (1H, partially hidden by solvent peak),3.00 (q, J = 7.4 Hz, 2H), 1.24 (t, J = 7.4 Hz, 3H) 47 2-(((3R,4S)-4-((4-chloro- phenyl)sulfonyl)- 3-hydroxy-3- (hydroxymethyl) pyrrolidin-1-yl)sulfonyl)benzonitrile

457.2 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.18 (d, J = 7.5 Hz, 1H), 8.02- 8.06(m, 1H), 7.89-8.00 (m, 2H), 7.72-7.80 (m, 4H), 5.68 (s, 1H), 4.93 (t, J= 5.4 Hz, 1H), 4.11 (dd, J = 7.5, 3.3 Hz, 1H), 3.66-3.78 (m, 2H), 3.63(d, J = 10.0 Hz, 2H), 3.49 (dd, J = 11.4, 3.1 Hz, 1H), 3.39 (d, J = 10.0Hz, 1H) 48 4-(((3R,4S)-4- ((4-chloro- phenyl)sulfonyl)- 3-hydroxy-3-(hydroxymethyl) pyrrolidin-1- yl)sulfonyl)-3- (difluoromethyl)benzonitrile

507.1 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.44 (s, 1H), 8.32 (d, J = 8.3 Hz,1H), 8.15 (d, J = 8.3 Hz, 1H), 7.80-7.86 (m, 2H), 7.74-7.79 (m, 2H),7.37-7.69 (m, 1H), 5.73 (s, 1H), 4.94 (t, J = 5.4 Hz, 1H), 4.09-4.15 (m,1H), 3.67-3.76 (m, 2H), 3.58-3.67 (m, 2H), 3.52 (dd, J = 11.3, 3.0 Hz,1H), 3.35 (d, J = 10.0 Hz, 1H) 49 4-(((3R,4S)-4- ((4-chloro-phenyl)sulfonyl)- 3-hydroxy-3- (hydroxymethyl) pyrrolidin-1-yl)sulfonyl)-3- ethoxybenzonitrile

501.1 ¹H NMR (400 MHz, DMSO-d₆) δ: 7.88 (d, J = 8.0 Hz, 1H), 7.71- 7.81(m, 5H), 7.55 (d, J = 8.0 Hz, 1H), 5.56 (s, 1H), 4.87 (t, J = 5.4 Hz,1H), 4.17-4.26 (m, 2H), 4.09 (dd, J = 7.5, 4.5 Hz, 1H), 3.76 (dd, J =11.0, 8.0 Hz, 1H), 3.61- 3.71 (m, 3H), 3.57 (dd, J = 11.2, 4.4 Hz, 1H),3.26 (d, J = 10.0 Hz, 1H), 1.33 (t, J = 6.9 Hz, 3H) 50 4-(((3R,4S)-4-((4-chloro- phenyl)sulfonyl)- 3-hydroxy-3- (hydroxymethyl) pyrrolidin-1-yl)sulfonyl)-3- cyclopropoxy- benzonitrile

513.3 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.00 (s, 1H), 7.89 (d, J = 8.3 Hz,1H), 7.73-7.82 (m, 4H), 7.61 (d, J = 8.0 Hz, 1H), 5.56 (s, 1H), 4.88 (t,J = 5.3 Hz, 1H), 4.03-4.12 (m, 2H), 3.56-3.75 (m, 4H), 3.52 (dd, J =11.3, 4.3 Hz, 1H), 3.20 (d, J = 10.0 Hz, 1H), 0.83-0.91 (m, 2H), 0.77(m, 2H) 51 4-(((3S,4R)-1- ((4-chloro-2- methoxyphenyl) sulfonyl)-4-hydroxy-4- (hydroxymethyl) pyrrolidin-3- yl)sulfonyl)benzonitrile

487.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.16 (d, J = 8.5 Hz, 2H), 7.98 (d, J= 8.8 Hz, 2H), 7.72 (d, J = 8.5 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.18(dd, J = 8.4, 1.9 Hz, 1H), 5.63 (s, 1H), 4.91 (t, J = 5.5 Hz, 1H), 4.16(dd, J = 7.8, 4.8 Hz, 1H), 3.87 (s, 3H), 3.74 (dd, J = 11.3, 8.0 Hz,1H), 3.51-3.69 (m, 4H), 3.17 (d, J = 10.0 Hz, 1H) 52 4-(((3S,4R)-1-((4-bromo-2- methoxyphenyl) sulfonyl)-4- hydroxy-4- (hydroxymethyl)pyrrolidin-3- yl)sulfonyl)benzonitrile

531.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.16 (d, J = 8.5 Hz, 2H), 7.97 (d, J= 8.8 Hz, 2H), 7.64 (d, J = 8.5 Hz, 1H), 7.50 (d, J = 1.5 Hz, 1H), 7.32(dd, J = 8.3, 1.8 Hz, 1H), 5.63 (s, 1H), 4.91 (t, J = 5.5 Hz, 1H), 4.16(dd, J = 7.7, 4.6 Hz, 1H), 3.87 (s, 3H), 3.74 (dd, J = 11.3, 7.8 Hz,1H), 3.50-3.69 (m, 4H), 3.17 (d, J = 10.0 Hz, 1H) 53 2-(((3R,4S)-3-hydroxy-3- (hydroxymethyl)- 4-((4- (trifluoromethyl) phenyl)sulfonyl)pyrrolidin-1- yl)sulfonyl)benzonitrile

491.1 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.19 (d, J = 7.3 Hz, 1H), 7.89- 8.11(m, 7H), 5.71 (s, 1H), 4.94 (t, J = 5.4 Hz, 1H), 4.18-4.24 (m, 1H),3.59-3.80 (m, 4H), 3.54 (dd, J = 11.5, 3.3 Hz, 1H), 3.38 (d, J = 10.0Hz, 1H) 54 3-chloro-4- (((3R,4S)-3- hydroxy-3- (hydroxymethyl)- 4-((4-(trifluoromethyl) phenyl)sulfonyl) pyrrolidin-1-yl)sulfonyl)benzonitrile

525.2 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.36 (s, 1H), 8.11-8.16 (m, 1H),8.04-8.11 (m, 5H), 5.77 (s, 1H), 4.95 (br s, 1H), 4.23 (dd, J = 7.4, 3.4Hz, 1H), 3.84 (dd, J = 11.4, 7.7 Hz, 1H), 3.60-3.79 (m, 4H), 3.38 (d, J= 10.0 Hz, 1H) 55 3- (difluoromethyl)- 4-(((3R,4S)-3- hydroxy-3-(hydroxymethyl)- 4-((4- (trifluoromethyl) phenyl)sulfonyl) pyrrolidin-1-yl)sulfonyl)benzonitrile

541.1 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.45 (s, 1H), 8.32 (d, J = 8.0 Hz,1H), 8.16 (d, J = 8.0 Hz, 1H), 8.01-8.11 (m, 4H), 7.36-7.69 (m, 1H),5.76 (s, 1H), 4.95 (t, J = 5.3 Hz, 1H), 4.19-4.26 (m, 1H), 3.59- 3.79(m, 4H), 3.55 (dd, J = 11.4, 3.1 Hz, 1H), 3.35 (d, J = 10.0 Hz, 1H,partially hidden by solvent peak) 56 4-(((3R,4S)-3- hydroxy-3-(hydroxymethyl)- 4-((4- (trifluoromethyl) phenyl)sulfonyl) pyrrolidin-1-yl)sulfonyl)-3- methoxybenzonitrile

521.2 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.01-8.09 (m, 4H), 7.89 (d, J = 8.0Hz, 1H), 7.81 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 5.60 (s, 1H), 4.87 (t,J = 5.4 Hz, 1H), 4.16 (dd, J = 7.4, 4.4 Hz, 1H), 3.92 (s, 3H), 3.79 (dd,J = 11.3, 7.8 Hz, 1H), 3.57-3.71 (m, 4H), 3.22 (d, J = 10.0 Hz, 1H) 573-cyclopropoxy- 4-(((3R,4S)-3- hydroxy-3- (hydroxymethyl)- 4-((4-(trifluoromethyl) phenyl)sulfonyl) pyrrolidin-1-yl)sulfonyl)benzonitrile

547.2 ¹H NMR (400 MHz, DMSO-d₆) δ: 7.98-8.12 (m, 5H), 7.89 (d, J = 8.3Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 5.59 (s, 1H), 4.89 (t, J = 5.3 Hz,1H), 4.16 (dd, J = 7.3, 4.8 Hz, 1H), 4.09 (br s, 1H), 3.53-3.78 (m, 5H),3.19 (d, J = 9.8 Hz, 1H), 0.82-0.90 (m, 2H), 0.76 (m, 2H) 584-(((3S,4R)-1- ((2-chloro-4-methyl- phenyl)sulfonyl)- 4-hydroxy-4-(hydroxymethyl) pyrrolidin-3- yl)sulfonyl)benzonitrile

470.9 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.16 (d, J = 8.0 Hz, 2H), 8.00 (d, J= 8.3 Hz, 2H), 7.85 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.37 (d, J = 8.0Hz, 1H), 5.69 (br s, 1H), 4.91 (br s, 1H), 4.21 (dd, J = 7.4, 3.9 Hz,1H), 3.63-3.78 (m, 4H), 3.53 (dd, J = 11.3, 3.8 Hz, 1H), 3.28- 3.34 (1H,partially hidden by solvent peak), 2.41 (s, 3H) 59 4-(((3S,4R)-1-((2-bromo-4- chlorophenyl)sulfonyl)- 4-hydroxy-4- (hydroxymethyl)pyrrolidin-3- yl)sulfonyl)benzonitrile

534.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.18 (d, J = 8.5 Hz, 2H), 8.10 (d, J= 2.0 Hz, 1H), 8.04 (d, J = 8.8 Hz, 2H), 7.98 (d, J = 8.5 Hz, 1H), 7.71(dd, J = 8.5, 2.0 Hz, 1H), 5.78 (s, 1H), 4.98 (t, J = 5.5 Hz, 1H), 4.25(dd, J = 7.7, 3.9 Hz, 1H), 3.62-3.83 (m, 4H), 3.59 (dd, J = 11.4, 3.9Hz, 1H), 3.30-3.34 (1H, partially hidden by solvent peak) 604-(((3S,4R)-1- ((2-bromo-4- methoxyphenyl) sulfonyl)-4- hydroxy-4-(hydroxymethyl) pyrrolidin-3- yl)sulfonyl)benzonitrile

531.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 9.26 (s, 1H), 8.63 (dd, J = 8.2, 1.4Hz, 1H), 8.22 (d, J = 8.3 Hz, 1H), 8.00 (s, 1H), 7.89 (d, J = 8.0 Hz,1H), 7.60 (d, J = 8.3 Hz, 1H), 5.66 (s, 1H), 4.86 (t, J = 5.4 Hz, 1H),4.33 (dd, J = 7.7, 3.9 Hz, 1H), 4.05-4.12 (m, 1H), 3.82-3.89 (m, 1H),3.72-3.79 (m, 1H), 3.57 (d, J = 5.5 Hz, 2H), 3.51 (d, J = 10.0 Hz, 1H),3.21 (d, J = 10.0 Hz, 1H), 0.73-0.92 (m, 4H) 61 3-cyclopropoxy-4-(((3R,4S)-3- hydroxy-3- (hydroxymethyl)- 4-((5- (trifluoromethyl)pyridin-2- yl)sulfonyl)pyrrolidin- 1-yl)sulfonyl) benzonitrile

548.3 ¹H NMR (400 MHz, DMSO-d₆) δ: 9.26 (s, 1H), 8.63 (dd, J = 8.2, 1.4Hz, 1H), 8.22 (d, J = 8.3 Hz, 1H), 8.00 (s, 1H), 7.89 (d, J = 8.0 Hz,1H), 7.60 (d, J = 8.3 Hz, 1H), 5.66 (s, 1H), 4.86 (t, J = 5.4 Hz, 1H),4.33 (dd, J = 7.7, 3.9 Hz, 1H), 4.04-4.12 (m, 1H), 3.82-3.89 (m, 1H),3.71-3.79 (m, 1H), 3.54- 3.61 (m, 2H), 3.51 (d, J = 10.0 Hz, 1H), 3.21(d, J = 10.0 Hz, 1H), 0.73-0.92 (m, 4H) 62 4-(((3S,4R)-1- ((2-chloro-4-fluorophenyl)sulfonyl)- 4-hydroxy-4- (hydroxymethyl) pyrrolidin-3-yl)sulfonyl)benzonitrile

475.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.18 (d, J = 8.8 Hz, 2H), 7.97 (d, J= 8.5 Hz, 2H), 7.77-7.87 (m, 2H), 7.55 (dd, J = 8.4, 1.9 Hz, 1H), 5.75(s, 1H), 4.96 (t, J = 5.5 Hz, 1H), 4.21 (dd, J = 7.7, 3.1 Hz, 1H),3.66-3.74 (m, 2H), 3.53-3.62 (m, 2H), 3.46 (dd, J = 11.8, 3.0 Hz, 1H),3.32 (d, J = 10.0 Hz, 1H) 63 4-(((3S,4R)-1- ((2,4-dichloro-5-fluorophenyl)sulfonyl)- 4-hydroxy-4- (hydroxymethyl) pyrrolidin-3-yl)sulfonyl)benzonitrile

509.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.15-8.20 (m, 3H), 8.07 (d, J = 8.3Hz, 2H), 8.00 (d, J = 9.0 Hz, 1H), 5.83 (s, 1H), 4.99 (t, J = 5.4 Hz,1H), 4.27 (dd, J = 7.5, 3.5 Hz, 1H), 3.83 (dd, J = 11.5, 7.5 Hz, 1H),3.59-3.76 (m, 4H), 3.38 (d, J = 10.0 Hz, 1H, partially hidden by solventpeak) 64 methyl 4- (((3S,4R)-1-((4- chloro-2- (difluoromethyl)phenyl)sulfonyl)- 4-hydroxy-4- (hydroxymethyl) pyrrolidin-3-yl)sulfonyl)benzimidate

540.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.15-8.23 (m, 2H), 7.88-8.01 (m, 5H),7.32-7.64 (m, 1H), 5.75 (s, 1H), 4.97 (t, J = 5.5 Hz, 1H), 4.16 (dd, J =7.5, 3.5 Hz, 1H), 3.91- 3.94 (m, 3H), 3.54-3.76 (m, 4H), 3.48 (dd, J =11.5, 3.5 Hz, 1H), 3.31 (m, 1H, partially hidden by solvent peak) 65(3R,4S)-1-((4- chloro-2- (difluoromethyl) phenyl)sulfonyl)-4-((4-chloro- phenyl)sulfonyl)-3- (hydroxymethyl) pyrrolidin-3-ol

516.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 7.96-8.01 (m, 2H), 7.90-7.95 (m, 1H),7.79-7.84 (m, 2H), 7.73-7.78 (m, 2H), 7.34-7.64 (m, 1H), 5.73 (s, 1H),4.97 (t, J = 5.5 Hz, 1H), 4.12 (dd, J = 7.8, 3.5 Hz, 1H), 3.60-3.75 (m,3H), 3.57 (d, J = 9.8 Hz, 1H), 3.47 (dd, J = 11.4, 3.6 Hz, 1H), 3.30 (d,J = 10.0 Hz, 1H) 66 2-(5-chloro-2- (((3R,4S)-4-((4-chlorophenyl)sulfonyl)- 3-hydroxy-3- (hydroxymethyl) pyrrolidin-1-yl)sulfonyl)phenyl) acetonitrile

505.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 7.94 (d, J = 8.5 Hz, 1H), 7.80- 7.86(m, 3H), 7.70-7.78 (m, 3H), 5.77 (s, 1H), 4.99 (t, J = 5.5 Hz, 1H), 4.29(s, 2H), 4.12 (dd, J = 7.5, 3.5 Hz, 1H), 3.71-3.78 (m, 1H), 3.56-3.69(m, 3H), 3.42 (dd, J = 11.2, 3.6 Hz, 1H), 3.29 (d, J = 9.8 Hz, 1H) 67(3R,4S)-4-((4- chlorophenyl)sulfonyl)- 1-((2-(difluoro-methoxy)pyridin-3- yl)sulfonyl)-3- (hydroxymethyl) pyrrolidin-3-ol

499.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.54 (dd, J = 5.0, 1.8 Hz, 1H), 8.30(dd, J = 7.8, 1.8 Hz, 1H), 7.54-7.96 (m, 5H), 7.50 (dd, J = 7.7, 4.9 Hz,1H), 5.69 (s, 1H), 4.96 (t, J = 5.5 Hz, 1H), 4.09 (dd, J = 7.7, 3.9 Hz,1H), 3.68-3.82 (m, 3H), 3.61-3.67 (m, 1H), 3.49 (dd, J = 11.5, 3.8 Hz,1H), 3.32 (d, J = 10.0 Hz, 1H, partially hidden by solvent peak) 683-chloro-4- (((3R,4S)-3- hydroxy-3- (hydroxymethyl)- 4-(thiazol-2-ylsulfonyl)pyrrolidin- 1-yl)sulfonyl) benzonitrile

464.1 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.34-8.40 (m, 2H), 8.24 (d, J = 2.3Hz, 1H), 8.11-8.18 (m, 1H), 8.02-8.08 (m, 1H), 5.85 (s, 1H), 5.01 (t, J= 5.1 Hz, 1H), 4.27 (dd, J = 6.8, 3.8 Hz, 1H), 3.88-4.00 (m, 2H),3.68-3.81 (m, 2H), 3.63 (d, J = 10.0 Hz, 1H), 3.38 (d, J = 10.0 Hz, 1H)69 2-fluoro-4- (((3S,4R)-1-((2- fluoro-4- (trifluoromethyl)phenyl)sulfonyl)- 4-hydroxy-4- (hydroxymethyl) pyrrolidin-3-yl)sulfonyl)benzonitrile

526.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.27 (dd, J = 8.2, 6.1 Hz, 1H), 8.10(d, J = 9.3 Hz, 1H), 8.03 (t, J = 7.4 Hz, 1H), 7.96 (dd, J = 8.5, 1.5Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.79 (dd, J = 8.2, 1.6 Hz, 1H), 5.83(s, 1H), 4.97 (br s, 1H), 4.29 (dd, J = 7.5, 2.8 Hz, 1H), 3.77 (dd, J =12.0, 7.5 Hz, 1H), 3.65-3.72 (m, 1H), 3.60 (d, J = 10.0 Hz, 2H), 3.52(dd, J = 11.9, 2.9 Hz, 1H), 3.38 (d, J = 10.3 Hz, 1H) 70 4-(((3S,4R)-1-((4-cyano-2-methyl- phenyl)sulfonyl)- 4-hydroxy-4- (hydroxymethyl)pyrrolidin-3- yl)sulfonyl)-2- fluorobenzonitrile

480.1 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.28 (dd, J = 8.0, 6.3 Hz, 1H),8.02-8.07 (m, 2H), 7.97-8.00 (m, 1H), 7.90-7.95 (m, 1H), 7.86 (dd, J =8.2, 1.6 Hz, 1H), 5.89 (s, 1H), 4.99 (br s, 1H), 4.32 (dd, J = 7.5, 3.3Hz, 1H), 3.68-3.76 (m, 2H), 3.57-3.66 (m, 2H), 3.50 (dd, J = 11.5, 3.3Hz, 1H), 3.33 (d, J = 9.8 Hz, 1H), 2.61 (s, 3H) 71 2-fluoro-4-(((3S,4R)-4- hydroxy-4- (hydroxymethyl)- 1-((2-methyl-4-(trifluoromethyl) phenyl)sulfonyl) pyrrolidin-3-yl)sulfonyl)benzonitrile

522.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.27 (dd, J = 8.0, 6.3 Hz, 1H),7.99-8.07 (m, 2H), 7.74-7.95 (m, 3H), 5.87 (s, 1H), 4.99 (t, J = 5.4 Hz,1H), 4.28-4.34 (m, 1H), 3.69- 3.77 (m, 2H), 3.56-3.67 (m, 2H), 3.49 (dd,J = 11.4, 3.4 Hz, 1H), 3.32 (m, 1H, partially hidden by solvent peak),2.67 (s, 3H) 72 2-fluoro-4- (((3S,4R)-4- hydroxy-4- (hydroxymethyl)-1-((2-methyl-6- (trifluoromethyl) pyridin-3- yl)sulfonyl)pyrrolidin-3-yl)sulfonyl) benzonitrile

523.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.47 (d, J = 8.0 Hz, 1H), 8.28 (dd, J= 8.0, 6.3 Hz, 1H), 8.05 (dd, J = 8.5, 1.5 Hz, 1H), 7.99 (d, J = 8.3 Hz,1H), 7.88 (dd, J = 8.0, 1.5 Hz, 1H), 5.91 (s, 1H), 5.00 (t, J = 5.4 Hz,1H), 4.34 (dd, J = 7.4, 3.4 Hz, 1H), 3.69-3.81 (m, 2H), 3.55-3.67 (m,3H), 3.38 (d, J = 10.0 Hz, 1H), 2.84 (s, 3H) 73 3-chloro-4-(((3R,4S)-4-((5- chlorothiazol-2- yl)sulfonyl)-3- hydroxy-3-(hydroxymethyl) pyrrolidin-1- yl)sulfonyl)benzonitrile

497.9 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.35 (d, J = 10.0 Hz, 2H), 8.12- 8.18(m, 1H), 8.04-8.08 (m, 1H), 5.90 (s, 1H), 5.04 (t, J = 4.6 Hz, 1H), 4.28(t, J = 5.1 Hz, 1H), 3.96 (d, J = 5.0 Hz, 2H), 3.69-3.78 (m, 2H), 3.63(d, J = 10.0 Hz, 1H), 3.37 (d, J = 10.0 Hz, 1H)

Example 744-(((3R,4S)-4-((4-bromophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile

Step 1:(S)-3-chloro-4-((3-hydroxy-4-methylenepyrrolidin-1-yl)sulfonyl)benzonitrile

To a solution of (S)-tert-butyl3-hydroxy-4-methylenepyrrolidine-1-carboxylate (10.5 g, 52.6 mmol) inDCM (50 mL) was added TFA (60 mL, 779 mmol) and the reaction mixture wasstirred at rt for 30 min and concentrated under reduced pressure to givea brown oil. The residue was dissolved in DCM (100 mL), cooled to 0° C.and treated with Et₃N (37 mL, 265 mmol) was added slowly (exothermic) toquench the excess TFA. 2-Chloro-4-cyanobenzene-1-sulfonyl chloride (12.4g, 52.6 mmol) was added and the mixture was and stirred for 1 h at rtbefore being diluted with DCM (300 mL), and washed with water (100 mL),0.1 N HCl (aq) (200 mL), and brine (100 mL). The organic layer was driedover MgSO₄, filtered and concentrated under reduced pressure to give thetitle compound as a brownish oil (17.0 g, 108% yield). MS (m/z) 281.0(M+H⁺—H₂O).

Step 2:(S)-1-((2-chloro-4-cyanophenyl)sulfonyl)-4-methylenepyrrolidin-3-ylmethanesulfonate

(S)-3-chloro-4-((3-hydroxy-4-methylenepyrrolidin-1-yl)sulfonyl)benzonitrile(17.0 g, 56.9 mmol) was dissolved in DCM (100 mL) and chilled to 0° C.in an ice bath. Et₃N (14 mL, 100 mmol) was added followed by a dropwiseaddition of methanesulfonyl chloride (5.5 mL, 71 mmol). The reactionmixture was allowed to warm to rt after addition was complete andstirred for 18 h. The reaction mixture was diluted with DCM (80 mL) andwashed with 0.1 N HCl (aq) (2×50 mL) followed by brine. The organiclayer was dried over MgSO₄, filtered and concentrated to give slightlybrown colored solid. The solid residue was triturated with 15% EtOAc inhexanes and filtered. The filter cake was washed with hexane and driedunder high vacuum to give the title compound as a beige solid (15.2 g,40.2 mmol, 71% yield). MS (m/z) 281.0 (M+H⁺-OMs).

Step 3:(R)-4-((3-((4-bromophenyl)thio)-4-methylenepyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile

To a solution of(S)-1-((2-chloro-4-cyanophenyl)sulfonyl)-4-methylenepyrrolidin-3-ylmethanesulfonate (4.54 g, 12.05 mmol) in DMF (80 mL) was added4-bromobenzenethiol (3.29 g, 17.40 mmol) followed by K₂CO₃ (1.85 g,13.39 mmol) and the reaction mixture was stirred at rt for 18 h. Themixture was diluted with EtOAc, washed with H₂O (2×) and brine, driedover Na₂SO₄, filtered and concentrated under reduced pressure. The cruderesidue was purified by flash column chromatography (SiO₂) eluting witha gradient of 0-40% EtOAc in hexanes. The product fractions were pooledand concentrated under reduced pressure to give the title compound as awhite solid (1.3 g, 20% yield). MS (m/z) 468.9 (M+H⁺).

Step 4:4-(((3R,4S)-4-((4-bromophenyl)thio)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile

To a solution of(R)-4-((3-((4-bromophenyl)thio)-4-methylenepyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile(1.3 g, 2.77 mmol) in THE (20 mL) and water (2 mL) was added NMO (50% inH₂O) (1.3 mL, 5.7 mmol) followed by OSO₄ (2.5% in t-BuOH, 1.4 mL, 0.11mmol) and the reaction mixture was stirred at rt for 3 h. The reactionmixture was stored in the freezer at −20° C. overnight. The reactionmixture was diluted with DCM, washed with 10% Na₂S₂O₃ (aq), 10% NaHCO₃(aq), H₂O, dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a dark semisolid. The crude isomer mixture was purifiedand separated by flash column chromatography (SiO₂) eluting with agradient of 0-75% EtOAc in hexanes to give the title compounds as theindividual cis and trans isomers. Cis-isomer: 1^(st) elutant, white foam(350 mg, 25% yield), ¹H NMR (400 MHz, DMSO-d₆) δ: 8.36 (s, 1H),8.12-8.16 (m, 1H), 8.05 (d, J=8.3 Hz, 1H), 7.51 (d, J=8.3 Hz, 2H), 7.33(d, J=8.5 Hz, 2H), 5.58 (s, 1H), 5.17 (t, J=5.3 Hz, 1H), 4.00 (t, J=8.5Hz, 1H), 3.76-3.84 (m, 1H), 3.62 (d, J=10.3 Hz, 1H), 3.44-3.54 (m, 2H),3.32-3.40 (m, 2H, partially hidden by solvent peak). Trans-isomer:2^(nd) eluant, white solid (808 mg, 58.0% yield), ¹H NMR (400 MHz,DMSO-d₆) δ: 8.35 (d, J=1.5 Hz, 1H), 8.10-8.15 (m, 1H), 8.03 (dd, J=8.3,1.5 Hz, 1H), 7.52 (d, J=8.5 Hz, 2H), 7.29 (d, J=8.5 Hz, 2H), 5.56 (s,1H), 4.98 (t, J=5.3 Hz, 1H), 3.96 (dd, J=10.2, 5.9 Hz, 1H), 3.82 (dd,J=5.8, 4.0 Hz, 1H), 3.60 (d, J=10.0 Hz, 1H), 3.45-3.57 (m, 2H),3.34-3.38 (1H, partially hidden by solvent peak), 3.31 (d, J=10.3 Hz,1H).

Step 5:4-(((3R,4S)-4-((4-bromophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-Chlorobenzonitrile

To a solution of4-(((3R,4S)-4-((4-bromophenyl)thio)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile(803 mg, 1.59 mmol) in DCM (20 mL) was added m-CPBA (1.79 g, 7.97 mmol)and the reaction mixture stirred at rt for 1 h. The reaction mixture wasdiluted with DCM, washed with 10% Na₂S₂O₃ (aq), H₂O, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude material waspurified by flash column chromatography (SiO₂), eluting with a gradientof 0-100% EtOAc in hexanes. The product fractions were pooled andconcentrated under reduced pressure to give the title compound as awhite foam (798 mg, 93% yield). ¹H NMR (400 MHz, DMSO-d₆) δ: 8.38 (d,J=1.5 Hz, 1H), 8.10-8.15 (m, 1H), 8.04-8.09 (m, 1H), 7.91 (d, J=8.6 Hz,2H), 7.75 (d, J=8.6 Hz, 2H), 5.79 (s, 1H), 4.99 (t, J=5.4 Hz, 1H), 4.14(dd, J=7.6, 3.3 Hz, 1H), 3.72-3.85 (m, 2H), 3.62-3.71 (m, 2H), 3.57 (dd,J=11.5, 3.4 Hz, 1H), 3.37 (d, J=9.9 Hz, 1H). MS (m/z) 535.0 (M+H⁺).

The following compounds were prepared using procedures analogous tothose described in Example 74 using appropriately substituted startingmaterials. As is appreciated by those skilled in the art, theseanalogous examples may involve variations in general reactionconditions.

MS (m/z) Ex. Name Structure (M + H⁺) ¹H NMR  75 4-(((3S,4S)-1- ((2,4-dichlorophenyl) sulfonyl)-4- hydroxy-4- (hydroxymethyl) pyrrolidin-3-yl)sulfonyl)-2- fluorobenzonitrile

508.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.24 (dd, J = 8.0, 6.3 Hz, 1H), 8.02(dd, J = 8.5, 1.5 Hz, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 2.3Hz, 1H), 7.87 (dd, J = 8.0, 1.5 Hz, 1H), 7.64 (dd, J = 8.5, 2.0 Hz, 1H),5.75 (s, 1H), 5.20 (t, J = 5.5 Hz, 1H), 4.25 (t, J = 8.3 Hz, 1H),3.75-3.87 (m, 2H), 3.58 (dd, J = 11.0, 5.5 Hz, 1H), 3.50 (d, J = 10.0Hz, 1H), 3.40 (dd, J = 11.2, 5.4 Hz, 1H), 3.30 (d, J = 10.0 Hz, 1H)  76(3S,4S)-4-((4- chloro-3- fluorophenyl) sulfonyl)-1-((2,4-dichlorophenyl) sulfonyl)-3- (hydroxymethyl) pyrrolidin-3-ol

517.7 ¹H NMR (400 MHz, DMSO-d₆) δ: 7.94-8.01 (m, 1H), 7.86-7.93 (m, 3H),7.69-7.74 (m, 1H), 7.64 (dd, J = 8.5, 2.0 Hz, 1H), 5.71 (s, 1H), 5.19(t, J = 5.5 Hz, 1H), 4.16 (t, J = 8.5 Hz, 1H), 3.73-3.84 (m, 2H), 3.58(dd, J = 11.3, 5.5 Hz, 1H), 3.50 (d, J = 10.3 Hz, 1H), 3.40 (dd, J =11.2, 5.4 Hz, 1H), 3.28 (d, J = 10.0 Hz, 1H)  77 2-(((3S,4S)-4- ((3,4-difluorophenyl) sulfonyl)-3- hydroxy-3- (hydroxymethyl) pyrrolidin-1-yl)sulfonyl)-5- (trifluoromethyl) benzonitrile

526.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.67 (d, J = 0.8 Hz, 1H), 8.25- 8.32(m, 1H), 8.19-8.24 (m, 1H), 7.85-7.94 (m, 1H), 7.69-7.80 (m, 2H), 5.66(s, 1H), 5.19 (t, J = 5.5 Hz, 1H), 4.16 (t, J = 8.5 Hz, 1H), 3.71-3.85(m, 2H), 3.49-3.62 (m, 2H), 3.41 (dd, J = 11.2, 5.4 Hz, 1H), 3.32-3.37(1H, partially hidden by solvent peak)  78 (3S,4S)-4-((4- chloro-3-fluorophenyl) sulfonyl)-1-((2- chloro-4- (trifluoromethyl)phenyl)sulfonyl)- 3-(hydroxymethyl) pyrrolidin-3-ol

551.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.13-8.21 (m, 2H), 7.86-7.95 (m, 3H),7.71 (d, J = 8.5 Hz, 1H), 5.69 (s, 1H), 5.16 (t, J = 5.5 Hz, 1H), 4.19(t, J = 8.4 Hz, 1H), 3.79-3.88 (m, 2H), 3.52-3.63 (m, 2H), 3.43 (dd, J =11.2, 5.1 Hz, 1H), 3.31-3.36 (1H, partially hidden by solvent peak)  794-(((3S,4S)-1- ((2,4- dichlorophenyl) sulfonyl)-4- hydroxy-4-(hydroxymethyl) pyrrolidin-3- yl)sulfonyl)-2,5- difluorobenzonitrile

526.6 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.36 (dd, J = 9.0, 4.8 Hz, 1H),7.94-8.01 (m, 2H), 7.89 (dd, J = 8.0, 5.3 Hz, 1H), 7.66 (dd, J = 8.5,2.3 Hz, 1H), 5.80 (s,1H), 5.22 (t, J = 5.5 Hz, 1H), 4.27 (t, J = 7.7 Hz,1H), 3.83-3.96 (m, 2H), 3.47-3.58 (m, 2H), 3.39 (dd, J = 11.4, 5.4 Hz,1H), 3.32-3.36 (1H, partially hidden by solvent peak)  80 2-chloro-4-(((3S,4S)-1-((2- chloro-4- (trifluoromethyl) phenyl)sulfonyl)-4-hydroxy-4- (hydroxymethyl) pyrrolidin-3- yl)sulfonyl)benzo nitrile

559.1 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.26 (d, J = 8.3 Hz, 1H), 8.15- 8.21(m, 3H), 7.99 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 5.78 (s,1H), 5.22 (t, J = 5.6 Hz, 1H), 4.30 (t, J = 8.3 Hz, 1H), 3.81-3.91 (m,2H), 3.60 (dd, J = 11.2, 5.6 Hz, 1H), 3.54 (d, J = 10.0 Hz, 1H), 3.42(dd, J = 11.2, 5.6 Hz, 1H), 3.32-3.36 (1H, Partially hidden by solventpeak)  81 4-(((3S,4S)-4- ((5- bromopyridin-2- yl)sulfonyl)-3- hydroxy-3-(hydroxymethyl) pyrrolidin-1- yl)sulfonyl)-3- chlorobenzonitrile

535.9 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.92 (s, 1H), 8.40 (d, J = 8.5 Hz,1H), 8.35 (s, 1H), 8.10-8.16 (m, 1H), 8.02-8.07 (m, 1H), 7.92 (d, J =8.3 Hz, 1H), 5.64 (s, 1H), 5.14 (t, J = 5.4 Hz, 1H), 4.35 (t, J = 8.3Hz, 1H), 4.05-4.13 (m, 1H), 3.85- 3.95 (m, 1H), 3.61 (dd, J = 11.0, 5.8Hz, 1H), 3.54 (d, J = 10.0 Hz, 1H), 3.42 (dd, J = 11.0, 5.3 Hz, 1H),3.35 (d, J = 10.0 Hz, 1H)  82 4-(((3S,4R)-1- ((2,4- dichlorophenyl)sulfonyl)-4- hydroxy-4- (hydroxymethyl) pyrrolidin-3- yl)sulfonyl)benzonitrile

491.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.18 (d, J = 8.5 Hz, 2H), 8.03 (d, J= 8.8 Hz, 2H), 7.94-7.99 (m, 2H), 7.65-7.70 (m, 1H), 5.78 (s, 1H), 4.98(t, J = 5.5 Hz, 1H), 4.24 (dd, J = 7.7, 3.6 Hz, 1H), 3.60- 3.82 (m, 4H),3.57 (dd, J = 11.4, 3.6 Hz, 1H), 3.30-3.35 (1H, partially hidden bysolvent peak)  83 4-(((3S,4R)-1- ((2,4- dichlorophenyl) sulfonyl)-4-hydroxy-4- (hydroxymethyl) pyrrolidin-3- yl)sulfonyl)-2-fluorobenzonitrile

509.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.28 (dd, J = 8.0, 6.3 Hz, 1H), 8.05(dd, J = 8.7,1.4 Hz, 1H), 7.95-8.00 (m, 2H), 7.86 (dd, J = 8.2.1.6 Hz,1H), 7.67 (dd, J = 8.5, 2.3 Hz, 1H), 5.83 (s, 1H), 4.97 (t, J = 5.4 Hz,1H), 4.31 (dd, J = 7.5, 3.5 Hz, 1H), 3.80 (dd, J = 11.5, 7.5 Hz, 1H),3.57-3.73 (m, 4H), 3.31-3.36 (1H, partially hidden by solvent peak)  845-chloro-2- (((3R,4S)-4-((4- cyanophenyl)sulf onyl)-3-hydroxy- 3-(hydroxymethyl) pyrrolidin-1- yl)sulfonyl)benzo nitrile

482.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.44 (d, J = 1.8 Hz, 1H), 8.18 (d, J= 8.8 Hz, 2H), 7.97-8.09 (m, 4H), 5.77 (s, 1H), 4.98 (t, J = 5.4 Hz,1H), 4.24 (dd, J = 7.7, 3.4 Hz, 1H), 3.75 (dd, J = 11.7, 7.7 Hz, 1H),3.52-3.70 (m, 4H), 3.37 (1H, partially hidden by solvent peak)  85(3R,4S)-1-((2,4- dichlorophenyl) sulfonyl)-4-((3,4- difluorophenyl)sulfonyl)-3- (hydroxymethyl) pyrrolidin-3-ol

501.9 ¹H NMR (400 MHz, CDCl₃) δ: 8.00 (d, J = 8.5 Hz, 1H), 7.70- 7.77(m, 2H), 7.59 (s,1H), 7.38- 7.50 (m, 2H), 4.41 (dd, J = 12.5, 5.0 Hz,1H), 3.73-3.90 (m, 3H), 3.66-3.72 (m,2H), 3.50 (d, J = 10.5 Hz, 1H),3.47 (s, 1H), 2.89 (dd, J = 9.3, 5.3 Hz, 1H)  86 4-(((3S,4R)-1- ((2,4-dichlorophenyl) sulfonyl)-4- hydroxy-4- (hydroxymethyl) pyrrolidin-3-yl)sulfonyl)-3- fluorobenzonitrile

508.9 ¹H NMR (400 MHz, CDCl₃) δ: 8.09 (t, J = 7.4 Hz, 1H), 7.98 (d, J =8.5 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.55-7.66 (m, 2H), 7.39 (dd, J =8.5, 1.8 Hz, 1H), 4.36 (d, J = 12.5 Hz, 1H), 3.93-4.04 (m, 2H),3.73-3.84 (m,2H), 3.67 (d, J = 11.0 Hz, 1H), 3.51 (d, J = 10.5 Hz, 1H) 87 4-(((3S,4R)-1- ((2,4- dichlorophenyl) sulfonyl)-4- hydroxy-4-(hydroxymethyl) pyrrolidin-3- yl)sulfonyl)-2,6- difluorobenzonitrile

527.1 ¹H NMR (400 MHz, CDCl₃) δ: 8.00 (d, J = 8.5 Hz, 1H), 7.65 (d, J =5.8 Hz, 2H), 7.59 (d, J = 1.8 Hz, 1H), 7.41 (dd, J = 8.5, 1.8 Hz, 1H),4.38 (dd, J = 12.5, 5.3 Hz, 1H), 3.77-3.94 (m, 3H), 3.69-3.76 (m, 2H),3.50 (t, J = 5.3 Hz, 2H), 2.69 (dd, J = 8.7, 5.1 Hz, 1H)  88(3R,4S)-4-((4- chloro-3- fluorophenyl) sulfonyl)-1-((2,4-dichlorophenyl) sulfonyl)-3- (hydroxymethyl) pyrrolidin-3-ol

518.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 7.87-8.00 (m, 4H), 7.61-7.74 (m, 2H),5.78 (s, 1H), 4.97 (t, J = 5.5 Hz, 1H), 4.22 (dd, J = 7.5, 3.5 Hz, 1H),3.69-3.82 (m, 2H), 3.62-3.68 (m, 2H), 3.56 (dd, J = 11.4, 3.6 Hz, 1H),3.31-3.37 (1H, partially hidden by solvent peak)  89 4-(((3S,4R)-1-((2-chloro-4- (trifluoromethyl) phenyl)sulfonyl)- 4-hydroxy-4-(hydroxymethyl) pyrrolidin-3- yl)sulfonyl)benzo nitrile

524.9 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.15-8.23 (m, 4H), 8.01-8.05 (m, 2H),7.97 (dd, J = 8.4,1.1 Hz, 1H), 5.81 (s, 1H), 4.99 (t, J = 5.4 Hz, 1H),4.25 (dd, J = 7.5, 3.5 Hz, 1H), 3.83 (dd, J = 11.4, 7.7 Hz, 1H),3.58-3.77 (m, 4H), 3.37 (d, J = 10.0 Hz, 1H, partially hidden by solventpeak)  90 4-(((3S,4S)-1- ((2-chloro-4- (trifluoromethyl)phenyl)sulfonyl)- 4-hydroxy-4- (hydroxymethyl) pyrrolidin-3-yl)sulfonyl)benzo nitrile

524.9 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.11-8.20 (m, 4H), 8.01-8.06 (m, 2H),7.92 (dd, J = 8.3, 1.3 Hz, 1H), 5.73 (s, 1H), 5.19 (t, J = 5.6 Hz, 1H),4.22 (t, J = 8.5 Hz, 1H), 3.77-3.88 (m, 2H), 3.59 (dd, J = 11.2, 5.6 Hz,1H), 3.53 (d, J = 10.3 Hz, 1H), 3.42 (dd, J = 11.2, 5.6 Hz, 1H),3.30-3.35 (1H, partially hidden by solvent peak)  91 4-(((3S,4R)-1-((2-chloro-4- (trifluoromethyl) phenyl)sulfonyl)- 4-hydroxy-4-(hydroxymethyl) pyrrolidin-3- yl)sulfonyl)-2,6- difluorobenzonitrile

560.9 ¹H NMR (400 MHz, CDCl₃) δ: 8.20 (d, J = 8.3 Hz, 1H), 7.84 (d, J =1.0 Hz, 1H), 7.63-7.72 (m, 3H), 4.40 (dd, J = 12.5, 5.3 Hz, 1H),3.89-3.97 (m, 1H), 3.71-3.88 (m, 4H), 3.57 (d, J = 1.0 Hz, 1H), 3.53 (d,J = 10.5 Hz, 1H), 2.74 (dd, J = 8.7, 5.1 Hz, 1H)  92 5-(((3S,4R)-1-((2-chloro-4- (trifluoromethyl) phenyl)sulfonyl)- 4-hydroxy-4-(hydroxymethyl) pyrrolidin-3- yl)sulfonyl) picolinonitrile

525.9 ¹H NMR (400 MHz, DMSO-d₆) δ: 9.17 (dd, J = 2.3, 0.8 Hz, 1H), 8.54(dd, J = 8.3, 2.3 Hz, 1H), 8.37 (dd, J = 8.3, 0.8 Hz, 1H), 8.17-8.24(m,2H), 7.97 (dd, J = 8.4, 1.1 Hz, 1H), 5.84 (s, 1H), 4.97 (t, J = 5.4Hz, 1H), 4.37 (dd, J = 7.5, 3.8 Hz, 1H), 3.84-3.92 (m, 1H), 3.76 (dd, J= 11.5, 3.8 Hz, 1H), 3.60-3.72 (m, 3H), 3.32- 3.39 (1H, partially hiddenby solvent peak)  93 2-(((3R,4S)-4- ((3,4- difluorophenyl) sulfonyl)-3-hydroxy-3- (hydroxymethyl) pyrrolidin-1- yl)sulfonyl)-5-(trifluoromethyl) benzonitrile

526.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.73 (s, 1H), 8.31-8.37 (m, 1H),8.22-8.27 (m, 1H), 7.96 (t, J = 7.5 Hz, 1H), 7.74-7.83 (m, 1H), 7.70 (brs, 1H), 5.79 (s, 1H), 4.99 (t, J = 5.4 Hz, 1H), 4.21 (dd, J = 7.5, 3.3Hz, 1H), 3.79 (dd, J = 11.7, 7.7 Hz, 1H), 3.55-3.73 (m, 4H), 3.42 (d, J= 10.0 Hz, 1H)  94 2-(((3R,4S)-3- hydroxy-3- (hydroxymethyl)- 4-((3,4,5-trifluorophenyl) sulfonyl)pyrrolidin- 1-yl)sulfonyl)-5-(trifluoromethyl) benzonitrile

544.9 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.71 (s, 1H), 8.29-8.35 (m, 1H),8.22-8.28 (m, 1H), 7.84 (t, J = 6.3 Hz, 2H), 5.81 (s, 1H), 4.94-4.98 (m,1H), 4.28 (d, J = 4.5 Hz, 1H), 3.82 (dd, J = 11.7, 7.7 Hz, 1H),3.57-3.73 (m,4H), 3.43 (d, J = 10.0 Hz, 1H)  95 4-(((3S,4R)-1- ((2,4-dichlorophenyl) sulfonyl)-4- hydroxy-4- (hydroxymethyl) pyrrolidin-3-yl)sulfonyl)-2,5- difluorobenzonitrile

526.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.40 (dd, J = 9.0, 4.8 Hz, 1H),7.94-8.01 (m, 2H), 7.88 (dd, J = 7.4, 5.4 Hz, 1H), 7.66 (dd, J = 8.5,2.0 Hz, 1H), 5.85 (s, 1 H), 4.94 (t, J = 5.0 Hz, 1H), 4.15 (dd, J = 7.4,3.1 Hz, 1H), 3.93 (dd, J = 11.7, 7.7 Hz, 1H), 3.75 (dd, J = 11.7, 3.1Hz, 1H), 3.54-3.66 (m, 3H), 3.30-3.37 (1H, partially hidden by solventpeak)  96 (3R,4S)-1-((2- chloro-4- (trifluoromethyl) phenyl)sulfonyl)-3-(hydroxymethyl)- 4-((4- (trifluoromethyl) phenyl)sulfonyl)pyrrolidin-3-ol

567.9 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.16-8.23 (m, 2H), 8.04-8.12 (m, 4H),7.96 (d, J = 8.3 Hz, 1H), 5.76 (s, 1H), 4.96 (t, J = 5.4 Hz, 1H), 4.24(dd, J = 7.3, 3.3 Hz, 1H), 3.84 (dd, J = 11.4, 7.7 Hz, 1H), 3.58-3.80(m, 4H), 3.38 (d, J = 9.8 Hz, 1H)  97 (3R,4S)-1-((2- chloro-4-(trifluoromethyl)p henyl)sulfonyl)- 4-((4- chlorophenyl) sulfonyl)-3-(hydroxymethyl) pyrrolidin-3-ol

533.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.19 (d, J = 3.5 Hz, 2H), 7.96 (d, J= 8.3 Hz, 1H), 7.81-7.87 (m, 2H), 7.76 (d, J = 8.5 Hz, 2H), 5.73 (s,1H), 4.95 (t, J = 5.4 Hz, 1H), 4.14 (dd, J = 7.2, 3.1 Hz, 1H), 3.74-3.86(m, 2H), 3.63-3.72 (m, 2H), 3.58 (dd, J = 11.3,3.3 Hz, 1H), 3.39 (d, J =9.8 Hz, 1H)  98 (3R,4S)-4-((4- chloro-3- fluorophenyl) sulfonyl)-1-((2-chloro-4- (trifluoromethyl) phenyl)sulfonyl)-3- (hydroxymethyl)pyrrolidin-3-ol

551.9 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.16-8.22 (m, 2H), 7.86-7.98 (m, 3H),7.69 (d, J = 8.5 Hz, 1H), 5.78 (s, 1H), 4.95 (t, J = 5.4 Hz, 1H), 4.23(dd, J = 7.3, 3.0 Hz, 1H), 3.84 (dd, J = 11.4, 7.7 Hz, 1H), 3.57-3.79(m, 4H), 3.39 (d, J = 9.8 Hz, 1H)  99 (3R,4S)-1-((2- chloro-4-(trifluoromethyl) phenyl)sulfonyl)- 4-((6- chloropyridin-3-yl)sulfonyl)-3- (hydroxymethyl) pyrrolidin-3-ol

534.9 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.84 (d, J = 2.0 Hz, 1H), 8.29 (dd, J= 8.5, 2.3 Hz, 1H), 8.17-8.23 (m, 2H), 7.96 (d, J = 8.3 Hz, 1H), 7.85(d, J = 8.3 Hz, 1H), 5.76 (s, 1H), 4.95 (t, J = 5.3 Hz, 1H), 4.28 (dd, J= 7.4, 3.6 Hz, 1H), 3.83- 3.91 (m, 1H), 3.63-3.76 (m, 4H), 3.36 (d, J =10.0 Hz, 1H) 100 4-(((3S,4R)-1- ((2-chloro-4- (trifluoromethyl)phenyl)sulfonyl)- 4-hydroxy-4- (hydroxymethyl) pyrrolidin-3-yl)sulfonyl)-2- methylbenzonitrile

538.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.16-8.22 (m, 2H), 8.09 (d, J = 8.3Hz, 1H), 7.94-7.99 (m, 2H), 7.80 (d, J = 8.0 Hz, 1H), 5.82 (s, 1H), 4.99(t, J = 5.4 Hz, 1H), 4.23 (dd, J = 7.5, 3.3 Hz, 1H), 3.62- 3.86 (m, 4H),3.58 (dd, J = 11.5, 3.3 Hz, 1H), 3.39 (d, J = 9.8 Hz, 1H), 2.59 (s, 3H)101 2-chloro-4- (((3S,4R)-1-((2- chloro-4- (trifluoromethyl)phenyl)sulfonyl)- 4-hydroxy-4- (hydroxymethyl) pyrrolidin-3-yl)sulfonyl)benzo nitrile

558.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.30 (d, J = 8.0 Hz, 1H), 8.17- 8.23(m, 3H), 7.97 (dd, J = 8.2, 1.6 Hz, 2H), 5.86 (s, 1H), 4.99 (t, J = 5.4Hz, 1H), 4.36 (dd, J = 7.5, 3.3 Hz, 1H), 3.85 (dd, J = 11.7, 7.4 Hz,1H), 3.61-3.75 (m, 4H), 3.38 (d, J = 9.8 Hz, 1H) 102 (3R,4S)-1-((2,4-dichlorophenyl) sulfonyl)-4-((4- fluorophenyl) sulfonyl)-3-(hydroxymethyl) pyrrolidin-3-ol

484.1 ¹H NMR (400 MHz, DMSO-d₆) δ: 7.87-8.01 (m, 4H), 7.67 (d, J = 8.5Hz, 1H), 7.53 (t, J = 8.8 Hz, 2H), 5.68 (s, 1H), 4.92 (t, J = 5.3 Hz,1H), 4.11 (dd, J = 7.4, 3.4 Hz, 1H), 3.73-3.81 (m, 2H), 3.63-3.70 (m,2H), 3.54 (dd, J = 11.3, 3.3 Hz, 1H), 3.34 (d, J = 10.0 Hz, 1H) 1032-chloro-5- (((3S,4R)-1- ((2,4- dichlorophenyl) sulfonyl)-4- hydroxy-4-(hydroxymethyl) pyrrolidin-3- yl)sulfonyl)benzo nitrile

524.9 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.47 (d, J = 1.8 Hz, 1H), 8.10- 8.16(m, 1H), 8.03-8.07 (m, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 1.8Hz, 1H), 7.67 (dd, J = 8.5, 1.8 Hz, 1H), 5.74 (s, 1H), 4.91 (t, J = 5.3Hz, 1H), 4.29 (dd, J = 7.5, 3.8 Hz, 1H), 3.81 (dd, J = 11.5, 7.8 Hz,1H), 3.59-3.74 (m, 4H), 3.30-3.35 (1H, partially hidden by solvent peak)104 3-chloro-4- (((3R,4S)-4-((4- ethylphenyl) sulfonyl)-3- hydroxy-3-(hydroxymethyl) pyrrolidin-1- yl)sulfonyl)benzo nitrile

485.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.37 (s, 1H), 8.10-8.15 (m, 1H),8.04-8.08 (m, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H),5.70 (s, 1H), 4.93 (t, J = 5.5 Hz, 1H), 4.01-4.06 (m, 1H), 3.75- 3.84(m, 2H), 3.64-3.71 (m, 2H), 3.54 (dd, J = 11.4, 2.6 Hz, 1H), 3.40 (d, J= 10.0 Hz, 1H), 2.74 (q, J = 7.5 Hz, 2H), 1.22 (t, J = 7.5 Hz, 3H) 1053-chloro-4- (((3R,4S)-3- hydroxy-3- (hydroxymethyl)- 4-((4-isopropylphenyl) sulfonyl) pyrrolidin-1- yl)sulfonyl)benzo nitrile

499.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.37 (s, 1H), 8.11-8.16 (m, 1H),8.02-8.09 (m, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H),5.70 (s, 1H), 4.93 (t, J = 5.4 Hz, 1H), 4.01-4.07 (m, 1H), 3.75- 3.85(m, 2H), 3.64-3.72 (m, 2H), 3.55 (dd, J = 11.3, 2.8 Hz, 1H), 3.40 (d, J= 9.8 Hz, 1H), 3.03 (dt, J = 13.7, 6.8 Hz, 1H), 1.24 (d, J = 6.8 Hz, 6H)106 3-chloro-4- (((3R,4S)-3- hydroxy-3- (hydroxymethyl)- 4-((4-propylphenyl) sulfonyl)pyrrolidin- 1-yl)sulfonyl)benzo nitrile

499.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.36 (s, 1H), 8.10-8.15 (m, 1H),8.03-8.08 (m, 1H), 7.72 (d, J = 7.8 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H),5.70 (s, 1H), 4.92 (br s, 1H), 4.00-4.06 (m, 1H), 3.74-3.85 (m, 2H),3.63-3.71 (m, 2H), 3.54 (dd, J = 11.3, 2.5 Hz, 1H), 3.40 (d, J = 10.0Hz, 1H), 2.68 (t, J = 7.4 Hz, 2H), 1.64 (sxt, J = 7.4 Hz, 2H), 0.91 (t,J = 7.3 Hz, 3H) 107 3-chloro-4- (((3R,4S)-4-((4- chloro-3- fluorophenyl)sulfonyl)-3- hydroxy-3- (hydroxymethyl) pyrrolidin-1- yl)sulfonyl)benzonitrile

508.9 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.36 (s, 1H), 8.10-8.16 (m,1H),8.04-8.09 (m, 1H), 7.89-7.98 (m, 2H), 7.69 (d, J = 8.3 Hz, 1H), 5.78 (s,1H), 4.94 (t, J = 5.0 Hz, 1H), 4.23 (dd, J = 7.3, 3.3 Hz, 1H), 3.83 (dd,J = 11.4, 7.7 Hz, 1H), 3.58-3.77 (m, 4H), 3.38 (d, J = 9.8 Hz, 1H) 108(3R,4S)-1-((2,4- dichlorophenyl) sulfonyl)-3- (hydroxymethyl)- 4-((2-(trifluoromethyl) pyrimidin-5- yl)sulfonyl) pyrrolidin-3-ol

536.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 9.53 (s, 2H), 7.94-8.04 (m, 2H), 7.68(dd, J = 8.5, 2.0 Hz, 1H), 5.84 (s, 1H), 5.00 (t, J = 5.4 Hz, 1H), 4.41(dd, J = 6.8, 5.0 Hz, 1H), 3.84-3.91 (m, 2H), 3.61-3.72 (m, 3H), 3.30(d, J = 10.0 Hz, 1H) 109 3-chloro-4- (((3S,4S)-4-((5- chloropyridin-2-yl)sulfonyl)-3- hydroxy-3- (hydroxymethyl) pyrrolidin-1-yl)sulfonyl)benzo nitrile

491.9 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.84 (d, J = 1.8 Hz, 1H), 8.35 (s,1H), 8.27 (dd, J = 8.5, 2.3 Hz, 1H), 8.11-8.16 (m, 1H), 7.97-8.07 (m,2H), 5.64 (s, 1H), 5.14 (t, J = 5.5 Hz, 1H), 4.36 (t, J = 8.3 Hz, 1H),4.05-4.14 (m, 1H), 3.84-3.94 (m, 1H), 3.61 (dd, J = 11.3, 5.8 Hz, 1H),3.54 (d, J = 10.3 Hz, 1H), 3.43 (dd, J = 11.0, 5.5 Hz, 1H), 3.35 (d, J =10.3 Hz, 1H) 110 3-chloro-4- (((3R,4S)-3- hydroxy-3- (hydroxymethyl)-4-((5- (trifluoromethyl) pyridin-2- yl)sulfonyl) pyrrolidin-1-yl)sulfonyl)benzo nitrile

526.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 9.26 (s, 1H), 8.64 (d, J = 8.3 Hz,1H), 8.37 (s, 1H), 8.24 (d, J = 8.3 Hz, 1H), 8.12-8.16 (m, 1H), 8.04-8.09 (m, 1H), 5.85 (s, 1H), 4.92 (t, J = 5.4 Hz, 1H), 4.39 (dd, J = 7.3,3.0 Hz, 1H), 3.91-4.00 (m, 1H), 3.80-3.88 (m, 1H), 3.56-3.69 (m, 3H),3.37 (d, J = 10.0 Hz, 1H, partially hidden by solvent peak) 1113-(((3R,4S)-4- ((4-chlorophenyl) sulfonyl)- 3-hydroxy-3- (hydroxymethyl)pyrrolidin-1- yl)sulfonyl) picolinonitrile

458.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 9.03 (dd, J = 4.8,1.5 Hz, 1H), 8.47(dd, J = 8.0, 1.5 Hz, 1H), 8.01 (dd, J = 8.2, 4.9 Hz, 1H), 7.73-7.85 (m,4H), 5.76 (s, 1H), 4.99 (t, J = 5.3 Hz, 1H), 4.14 (dd, J = 7.5, 3.3 Hz,1H), 3.78 (dd, J = 11.8, 7.5 Hz, 1H), 3.52-3.73 (m, 4H), 3.44 (d, J =10.3 Hz, 1H) 112 3-chloro-4- (((3R,4S)-3- hydroxy-3- (hydroxymethyl)-4-((2- (trifluoromethyl) pyrimidin-5- yl)sulfonyl) pyrrolidin-1-yl)sulfonyl)benzo nitrile

527.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 9.53 (s, 2H), 8.39 (s, 1H), 8.13-8.19 (m, 1H), 8.04-8.10 (m, 1H), 5.90 (s, 1H), 5.02 (t, J = 5.3 Hz, 1H),4.41-4.46 (m, 1H), 3.85-3.97 (m, 2H), 3.67 (d, J = 7.5 Hz, 3H),3.32-3.40 (1H, partially hidden by solvent peak) 113 4-(((3R,4S)-4-((5-bromopyridin-2- yl)sulfonyl)-3- hydroxy-3- (hydroxymethyl) pyrrolidin-1-yl)sulfonyl)-3- chlorobenzonitrile

536.2 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.97 (s, 1H), 8.45 (d, J = 8.3 Hz,1H), 8.35 (s, 1H), 8.12-8.16(01, 1H), 8.03-8.08 (m, 1H), 7.96 (d, J =8.5 Hz, 1H), 4.28-4.33 (m, 1H), 3.88-3.97 (m, 1H), 3.79 (dd, J = 11.5,2.8 Hz, 1H), 3.56-3.70 (m, 3H), 3.37 (d, J = 10.0 Hz, 1H, partiallyhidden by solvent peak) 114 (3R,4S)-1-((2,4- dichlorophenyl)sulfonyl)-4-((3,4- dichlorophenyl) sulfonyl)-3- (hydroxymethyl)pyrrolidin-3-ol

533.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.05 (s, 1H), 7.92-8.00 (m, 3H), 7.80(d, J = 8.5 Hz, 1H), 7.64- 7.69 (m, 1H), 5.74 (s, 1H), 4.94 (t, J =5.3Hz, 1H), 4.25 (dd, J = 7.3, 3.3 Hz, 1H), 3.63-3.84 (m, 4H), 3.56 (dd,J = 11.3, 3.3 Hz, 1H), 3.35 (d, J = 10.3 Hz, 1H, partially hidden bysolvent peak) 115 (3S,4S)-1-((2,4- dichlorophenyl) sulfonyl)-4-((3,4-dichlorophenyl) sulfonyl)-3- (hydroxymethyl) pyrrolidin-3-ol

533.7 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.06 (d, J = 1.8 Hz, 1H), 7.88- 8.00(m, 3H), 7.79-7.84 (m, 1H), 7.63 (dd, J = 8.5, 1.8 Hz, 1H), 5.70 (s,1H), 5.16 (t, J = 5.5 Hz, 1H), 4.18 (t, J = 8.4 Hz, 1H), 3.79 (d, J =8.3 Hz, 2H), 3.58 (dd, J = 11.0, 5.5 Hz, 1H), 3.50 (d, J = 10.3 Hz, 1H),3.40 (dd, J = 11.2, 5.4 Hz, 1H), 3.29 (d, J = 10.3 Hz, 1H, partiallyhidden by solvent peak) 116 (3R,4S)-1-((2,4- dichlorophenyl)sulfonyl)-3- (hydroxymethyl)- 4-((5- (trifluoromethyl) pyridin-2-yl)sulfonyl) pyrrolidin-3-ol

534.8 ¹H NMR (400 MHz, DMSO-d₆) δ: 9.25 (s, 1H), 8.63 (d, J = 8.3 Hz,1H), 8.24 (d, J = 8.0 Hz, 1H), 7.92-8.03 (m, 2H), 7.66 (dd, J = 8.5, 2.0Hz, 1H), 5.80 (s, 1H), 4.90 (br s, 1H), 4.38 (dd, J = 7.5, 3.3 Hz, 1H),3.87-3.97 (m, 1H), 3.78-3.85 (m, 1H), 3.57-3.69 (m, 3H), 3.29-3.39 (1H,partially hidden by solvent peak) 117 2-(((3R,4S)-4-((4- chlorophenyl)sulfonyl)-3- hydroxy-3- (hydroxymethyl) pyrrolidin-1- yl)sulfonyl)-5-(trifluoromethyl) benzonitrile

524.9 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.73 (s, 1H), 8.35 (d, J = 8.3 Hz,1H), 8.24 (d, J = 8.3 Hz, 1H), 7.79 (q, J = 8.8 Hz, 4H), 5.75 (s, 1H),4.99 (t, J = 5.4 Hz, 1H), 4.14 (dd, J = 7.5, 3.0 Hz, 1H), 3.52- 3.81 (m,5H), 3.41 (d, J = 10.3 Hz, 1H) 118 (3R,4S)-1-((2,4- dichlorophenyl)sulfonyl)-3- (hydroxymethyl)- 4-((6- (trifluoromethyl) pyridin-3-yl)sulfonyl) pyrrolidin-3-ol

534.9 ¹H NMR (400 MHz, DMSO-d₆) δ: 9.22 (s, 1H), 8.57 (d, J = 8.3 Hz,1H), 8.24 (d, J = 8.3 Hz, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.95 (d, J =1.8 Hz, 1H), 7.67 (dd, J = 8.5, 1.8 Hz, 1H), 5.76 (s, 1H), 4.94 (t, J =5.4 Hz, 1H), 4.35-4.41 (m, 1H), 4.36 (dd, J = 7.4, 4.1 Hz, 1H),3.81-3.89 (m, 1H), 3.74 (dd, J = 11.2, 3.9 Hz, 1H), 3.63-3.70 (m, 3H),3.27-3.34 (1H, partially hidden by solvent peak)

Example 1193-chloro-4-(((3R,4S)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxy-3-((S)-1-hydroxyethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile

Step 1: N-allyl-2-chloro-4-cyanobenzenesulfonamide

To a solution 2-chloro-4-cyanobenzene-1-sulfonyl chloride (2.6 g, 11.0mmol) and K₂CO₃ (10 g, 72.4 mmol) in water (50 mL) and DCM (50 mL) wasadded prop-2-en-1-amine (1.26 g, 22.0 mmol) and the reaction mixture wasstirred at rt overnight. The organic layer was separated and washed withbrine, dried over Na₂SO₄, filtered, and concentrated to give the titlecompound as a yellow oil (2.8 g, 99% yield). MS (m/z) 257.0 (M+H⁺).

Step 2:N-allyl-N-(3-((tert-butyldimethylsilyl)oxy)-2-methylenebutyl)-2-chloro-4-cyanobenzenesulfonamide

A mixture of N-allyl-2-chloro-4-cyanobenzenesulfonamide (2.6 g, 10.1mmol), ((3-(bromomethyl)but-3-en-2-yl)oxy)(tert-butyl)dimethylsilane(4.1 g, 12.2 mmol) and K₂CO₃ (1.40 g, 10.1 mmol) in CH₃CN (75 mL) wasstirred at 55° C. for 72 h. The reaction mixture was filtered, thefiltrate was concentrated and the crude product was purified by flashcolumn chromatography (SiO₂) eluting with a gradient of 0-50% EtOAc inhexanes. The desired product fractions were pooled and concentrated togive the title compound as a clear oil (3.3 g, 72% yield). MS (m/z)477.2 (M+Na⁺).

Step 3:4-((3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-2,5-dihydro-1H-pyrrol-1-yl)sulfonyl)-3-chlorobenzonitrile

A mixture ofN-allyl-N-(3-((tert-butyldimethylsilyl)oxy)-2-methylenebutyl)-2-chloro-4-cyanobenzenesulfonamide(2.8 g, 6.15 mmol) and Grubbs Catalyst, 2^(nd) Generation (300 mg, 0.353mmol) in DCM (60 mL) was stirred at rt overnight. The reaction mixturewas filtered and the filtrate purified by flash column chromatography(SiO₂) eluting with a gradient of 0-40% EtOAc in hexanes. The desiredproduct fractions were pooled and concentrated to give the titlecompound as a clear gooey film (2.07 g, 79% yield). MS (m/z) 427.2(M+H⁺).

Step 4:4-((1-(1-((tert-butyldimethylsilyl)oxy)ethyl)-6-oxa-3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-3-chlorobenzonitrile

To a solution of4-((3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-2,5-dihydro-1H-pyrrol-1-yl)sulfonyl)-3-chlorobenzonitrile(2.07 g, 4.85 mmol) in DCM (50 mL) was added portionwise m-CPBA (3.26 g,14.5 mmol) and the reaction mixture was stirred at rt overnight. Thereaction was quenched with sat'd NaHSO₃ (aq) bisulfate, followed bysat'd NaHCO₃ (aq) and the mixture stirred for 30 min. The organic layerwas separated and the aqueous layer was extracted with EtOAc (150 ml).The combined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated. The crude residue was purified by flashcolumn chromatography (SiO₂) eluting with a gradient of 0-40% EtOAc inhexanes. The desired product fractions were pooled and concentrated togive the title compound as a 4:1 mixture (by NMR) of diastereomers (2.1g, 98% yield). MS (m/z) 443.2 (M+H⁺).

Step 5:4-(((3R,4S)-3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-((5-chloropyridin-2-yl)thio)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrileand4-(((3S,4R)-3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-((5-chloropyridin-2-yl)thio)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile

A mixture of4-((1-(1-((tert-butyldimethylsilyl)oxy)ethyl)-6-oxa-3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-3-chlorobenzonitrile(2.1 g, 4.74 mmol), 5-chloropyridine-2-thiol (0.76 g, 5.21 mmol) andCs₂CO₃ (0.77 g, 2.37 mmol) in NMP (10 mL) subjected to microwaveirradiation at 65° C. for 1 h. The reaction mixture was diluted withEtOAc, washed with water (2×) and brine (2×), dried over Na₂SO₄,filtered and concentrated. The crude residue was purified by flashcolumn chromatography (SiO₂) eluting with a gradient of 0-100% EtOAc inhexanes. The desired product fractions were pooled and concentrated togive the title compound as a white solid (2.0 g, 72% yield). MS (m/z)588.0 (M+H⁺).

Step 6:4-(((3R,4S)-3-((R)-1-((tert-butyldimethylsilyl)oxy)ethyl)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrileand4-(((3S,4R)-3-((S)-1-((tert-butyldimethylsilyl)oxy)ethyl)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrileor4-(((3R,4S)-3-((S)-1-((tert-butyldimethylsilyl)oxy)ethyl)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrileand4-(((3S,4R)-3-((R)-1-((tert-butyldimethylsilyl)oxy)ethyl)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile

To a solution of the isomeric mixture4-(((3R,4S)-3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-((5-chloropyridin-2-yl)thio)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrileand4-(((3S,4R)-3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-((5-chloropyridin-2-yl)thio)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile(1.07 g, 1.82 mmol), in DCM (26.0 mL), was added m-CPBA (1.26 g, 7.27mmol), portionwise, and the reaction mixture was stirred at rt for 46 h.The reaction was quenched with sat'd NaHSO₃ (aq) (100 mL) and themixture was stirred for 1 h. The organic layer was removed, washed withsat'd NaHCO₃ (aq) (100 mL) and concentrated. The crude products werepurified and the diasteomers separated by flash column chromatography(SiO₂) eluting with a gradient of 0-50% EtOAc in hexanes. The individualracemic diastereomers of the title compounds were isolated. Racemicmixture of 4-(3R,4S)-3-(R) and 4-(3S,4R)-3-(S) Isomers: 1^(st) eluant,yellow oil (792 mg, 67% yield): ¹H NMR (400 MHz, DMSO-d₆) δ: 8.89 (d,J=2.0 Hz, 1H), 8.31-8.36 (m, 2H), 8.09-8.14 (m, 1H), 8.03-8.08 (m, 1H),7.91 (d, J=8.3 Hz, 1H), 5.39 (s, 1H), 4.33 (q, J=6.2 Hz, 1H), 4.27 (d,J=6.5 Hz, 1H), 3.82 (dd, J=11.9, 6.7 Hz, 1H), 3.66 (d, J=9.8 Hz, 1H),3.46 (d, J=12.0 Hz, 1H), 3.30-3.35 (m, 1H. partially hidden by solventpeak), 1.19 (d, J=6.5 Hz, 3H), 0.86 (s, 9H), 0.09 (d, J=9.0 Hz, 6H). MS(m/z) 620.0 (M+H+). Racemic mixture of 4-(3R,4S)-3-(S) and4-(3S,4R)-3-(R) Isomers: 2^(nd) eluant, yellow oil (180 mg, 15.1%yield): ¹H NMR (400 MHz, DMSO-d₆) δ: 8.91 (d, J=2.0 Hz, 1H), 8.31-8.41(m, 2H), 8.08 (d, J=0.8 Hz, 2H), 7.93 (d, J=8.3 Hz, 1H), 5.77 (s, 1H,partially hidden by solvent peak), 4.35 (q, J=5.9 Hz, 1H), 4.12 (d,J=6.5 Hz, 1H), 3.90 (dd, J=12.2, 6.9 Hz, 1H), 3.68 (d, J=10.3 Hz, 1H),3.53-3.63 (m, 2H), 1.08 (d, J=6.0 Hz, 3H), 0.78-0.91 (m, 9H), 0.06 (d,J=1.5 Hz, 6H). MS (m/z) 620.0 (M+H⁺).

Step 7:3-chloro-4-(((3R,4S)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxy-3-((S)-1-hydroxyethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile

To a solution of the racemic mixture4-(((3R,4S)-3-((S)-1-((tert-butyldimethylsilyl)oxy)ethyl)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrileand4-(((3S,4R)-3-((S)-1-((tert-butyldimethylsilyl)oxy)ethyl)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile(478 mg, 0.769 mmol) in acetic acid (3.4 mL) was added TBAF (4.34 mL,4.34 mmol) and the reaction mixture was stirred at 65° C. overnight. Thereaction mixture was diluted with EtOAc, washed with NH₄Cl (aq), driedover Na₂SO₄, filtered and concentrated. The crude product was purifiedby flash column chromatography (SiO₂) eluting with a gradient of 0-100%EtOAc in hexanes. The enantiomers were then separated using preparativechiral HPLC (Chiralpak IF, 30×250 mm) eluting with MeOH/CH₃CN (90/100)at a flowrate of 45 mL/min.

3-chloro-4-(((3R,4S)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxy-3-((S)-1-hydroxyethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile:1^(st) eluant, white solid (85 mg, 21% yield): ¹H NMR (400 MHz, DMSO-d₆)δ: 8.86 (d, J=2.0 Hz, 1H), 8.37 (d, J=1.5 Hz, 1H), 8.29 (dd, J=8.4, 2.4Hz, 1H), 8.13-8.18 (m, 1H), 8.02-8.10 (m, 2H), 5.48 (d, J=1.3 Hz, 1H),4.35 (d, J=6.5 Hz, 1H), 4.31 (d, J=5.0 Hz, 1H), 4.00-4.07 (m, 1H),3.90-3.98 (m, 2H), 3.48 (dd, J=10.0, 1.3 Hz, 1H), 3.25 (d, J=9.8 Hz,1H), 0.97 (d, J=6.0 Hz, 3H). MS (m/z) 506.1 (M+H⁺).

3-chloro-4-(((3S,4R)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxy-3-((R)-1-hydroxyethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile:2^(nd) eluant, white solid (85 mg, 21% yield): ¹H NMR (400 MHz, DMSO-d₆)δ: 8.86 (d, J=2.0 Hz, 1H), 8.36 (d, J=1.5 Hz, 1H), 8.29 (dd, J=8.4, 2.4Hz, 1H), 8.13-8.19 (m, 1H), 8.01-8.09 (m, 2H), 5.49 (d, J=1.3 Hz, 1H),4.35 (d, J=6.5 Hz, 1H), 4.31 (d, J=5.3 Hz, 1H), 4.00-4.06 (m, 1H),3.90-3.98 (m, 2H), 3.48 (dd, J=9.9, 1.1 Hz, 1H), 3.25 (d, J=9.8 Hz, 1H),0.93-0.99 (m, 3H). MS (m/z) 506.1 (M+H⁺).

Example 1203-chloro-4-(((3R,4S)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxy-3-((R)-1-hydroxyethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile

To a solution of the racemic mixture4-(((3R,4S)-3-((R)-1-((tert-butyldimethylsilyl)oxy)ethyl)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrileand4-(((3S,4R)-3-((S)-1-((tert-butyldimethylsilyl)oxy)ethyl)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile(180 mg, 0.769 mmol) in acetic acid (3 mL) was added TBAF (12 mL, 12mmol) and the reaction mixture was stirred at 65° C. overnight. Thereaction mixture was diluted with EtOAc, washed with NH₄Cl (aq), driedover Na₂SO₄, filtered and concentrated. The crude product was purifiedby flash column chromatography (SiO₂) eluting with a gradient of 0-100%EtOAc in hexanes. The enantiomers were then separated using preparativechiral SFC (Chiralpak AS, 20×250 mm) eluted with CO₂/EtOH (80/20) at aflowrate of 60 G/min.

3-chloro-4-(((3R,4S)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxy-3-((R)-1-hydroxyethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile:1^(st) eluant, white solid (16 mg, 11% yield) (>99% ee): ¹H NMR (400MHz, DMSO-d₆) δ: 8.91 (d, J=2.3 Hz, 1H), 8.32-8.39 (m, 2H), 8.09-8.14(m, 1H), 8.03-8.08 (m, 1H), 7.99 (d, J=8.5 Hz, 1H), 5.70 (s, 1H), 4.99(d, J=6.0 Hz, 1H), 4.07-4.17 (m, 2H), 3.92 (dd, J=12.0, 7.0 Hz, 1H),3.69 (d, J=10.5 Hz, 1H), 3.63 (d, J=11.5 Hz, 1H), 3.50 (d, J=10.3 Hz,1H), 1.07 (d, J=6.0 Hz, 3H). MS (m/z) 506.0 (M+H⁺).

3-chloro-4-(((3S,4R)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxy-3-((S)-1-hydroxyethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile:2^(nd) eluant, white solid (17 mg, 12% yield) (>99% ee): ¹H NMR (400MHz, DMSO-d₆) δ: 8.91 (d, J=2.3 Hz, 1H), 8.32-8.39 (m, 2H), 8.09-8.14(m, 1H), 8.03-8.08 (m, 1H), 7.99 (d, J=8.5 Hz, 1H), 5.70 (s, 1H), 4.99(d, J=6.3 Hz, 1H), 4.12 (dt, J=9.7, 5.8 Hz, 2H), 3.92 (dd, J=12.0, 6.8Hz, 1H), 3.69 (d, J=10.5 Hz, 1H), 3.63 (d, J=11.8 Hz, 1H), 3.50 (d,J=10.3 Hz, 1H), 1.07 (d, J=6.3 Hz, 3H). MS (m/z) 506.1 (M+H⁺).

Example 1214-(((3S,4S)-3-(aminomethyl)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile

Step 1: (R)-tert-butyl3-((5-chloropyridin-2-yl)thio)-4-methylenepyrrolidine-1-carboxylate

To a solution of (S)-tert-butyl3-hydroxy-4-methylenepyrrolidine-1-carboxylate (2.0 g, 10.0 mmol) in DCM(30 mL) was added Et₃N (2.1 mL, 15.1 mmol), followed by a dropwiseaddition of MsCl (0.94 mL, 12.1 mmol). The mixture was stirred for 30min, diluted with water and extracted with DCM. The organic layer waswashed with water, dried over MgSO₄, filtered and the filtrate wasconcentrated. The intermediate residue (S)-tert-butyl3-methylene-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate wasdissolved in DMF (100 mL) and 5-chloropyridine-2-thiol (1.46 g, 10.0mmol) was added, followed by K₂CO₃ (2.08 g, 15.1 mmol). The reactionmixture was stirred for 1h at rt before being diluted with water andextracted with EtOAc. The organic extract was washed with water, driedover MgSO₄, filtered and the filtrate was concentrated. The crudeproduct was purified by chromatography (SiO₂) using a gradient of 0-15%EtOAc in hexanes to give the title compound as a clear colorless oil(3.0 g, 91% yield). MS (m/z) 327.0 (M+H⁺).

Step 2: (4S)-tert-butyl4-((5-chloropyridin-2-yl)thio)-3-hydroxy-3-(hydroxymethyl)pyrrolidine-1-carboxylate

A mixture of (R)-tert-butyl3-((5-chloropyridin-2-yl)thio)-4-methylenepyrrolidine-1-carboxylate (3.0g, 9.2 mmol), OsO₄ (2.5% in t-BuOH, 4.61 mL, 0.367 mmol), and NMO (2.8mL, 14 mmol) in THE (30 mL) was stirred at rt for 2 h. The mixture wasquenched with saturated Na₂SO₃ (aq) (40 mL) and extracted with EtOAc (40mL). The organic extract was washed with brine, dried over anhydrousMgSO₄, filtered and the filtrate was concentrated. The crude productwhich was purified by flash column chromatography (SiO₂) eluting with agradient of 0-55% EtOAc in hexanes to give a mixture of the cis andtrans isomers (45/55 by NMR and HPLC) of the title compound as a clearcolorless oil (2.58 g, 78% yield. MS (m/z) 261.1 (M+H⁺-Boc).

Step 3: Cis-Isomer: (5S,9S)-tert-butyl9-((5-chloropyridin-2-yl)thio)-2,2-dimethyl-1,3-dioxa-7-azaspiro[4.4]nonane-7-carboxylateor Trans-Isomer: (5R,9S)-tert-butyl9-((5-chloropyridin-2-yl)thio)-2,2-dimethyl-1,3-dioxa-7-azaspiro[4.4]nonane-7-carboxylate

A mixture of (4S)-tert-butyl4-((5-chloropyridin-2-yl)thio)-3-hydroxy-3-(hydroxymethyl)pyrrolidine-1-carboxylate(2.58 g, 7.15 mmol), 2,2-dimethoxypropane (2.64 mL, 21.5 mmol), andp-toluenesulfonic acid monohydrate (0.136 g, 0.715 mmol) in DCM (20 mL)was stirred at rt for 30 min. The reaction mixture was diluted withwater and extracted with DCM. The organic extract was washed with brine,dried over anhydrous MgSO₄, filtered and the filtrate was concentrated.The crude product was purified by flash column chromatography (SiO₂)eluting with a gradient of 0-25% EtOAc in hexanes to give the titlecompounds as separated cis and trans isomers. Cis-isomer: 2^(nd) eluent,clear colorless oil (1.1 g, 38% yield), ¹H NMR (400 MHz, DMSO-d₆) δ:8.51 (s, 1H), 7.79 (d, J=6.5 Hz, 1H), 7.44 (d, J=8.5 Hz, 1H), 4.31-4.46(m, 1H), 3.92-4.15 (m, 3H, partially hidden by solvent peak), 3.45-3.62(m, 2H), 3.15-3.28 (m, 1H), 1.33-1.48 (m, 15H). MS (m/z) 345.2(M+H⁺-Boc). Trans-isomer: 1^(st) eluent, clear colorless oil (1.1 g,38.4% yield), ¹H NMR (400 MHz, DMSO-d₆) δ: 8.55 (s, 1H), 7.83 (d, J=8.5Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 4.37 (d, J=15.3 Hz, 1H), 3.97-4.17 (m,2H, partially hidden by solvent peak), 3.79-3.96 (m, 1H), 3.51 (d,J=11.0 Hz, 1H), 3.33-3.44 (m, 2H, partially hidden by solvent peak),1.29-1.53 (m, 15H). MS (m/z) 345.2 (M+H⁺-Boc).

Step 4:3-chloro-4-(((3R,4S)-4-((5-chloropyridin-2-yl)thio)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile

A solution of (5R,9S)-tert-butyl9-((5-chloropyridin-2-yl)thio)-2,2-dimethyl-1,3-dioxa-7-azaspiro[4.4]nonane-7-carboxylate(800 mg, 2.0 mmol) in TFA (7.8 mL, 100 mmol) and DCM (3 mL) was stirredat rt for 30 min. The mixture was concentrated, the residue was basifiedwith saturated NaHCO₃ (aq), and the resulting suspension was dissolvedwith the addition THE (10 mL). 2-chloro-4-cyanobenzene-1-sulfonylchloride (0.92 g, 3.0 mmol) in THE (10 mL) was added dropwise and themixture was stirred for at rt for 30 min. The mixture was diluted withwater and extracted with EtOAc. The organic extract was washed withbrine, dried over anhydrous MgSO₄, filtered and the filtrate wasconcentrated. The crude product was purified by flash columnchromatography (SiO₂) eluting with a gradient of 0-60% EtOAc in hexanes.The product fractions were pooled and concentrated to give the titlecompound as a semi-solid (850 mg, 93% yield). MS (m/z) 460.1 (M+H⁺).

Step 5:4-(((3S,4S)-3-(azidomethyl)-4-((5-chloropyridin-2-yl)thio)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile

To a solution of3-chloro-4-(((3R,4S)-4-((5-chloropyridin-2-yl)thio)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile(280 mg, 0.61 mmol) in DCM (8 mL) was added Et₃N (0.15 mL, 1.1 mmol),followed by MsCl (0.057 mL, 0.73 mmol) and the reaction mixture wasstirred at rt for 10 min. The mixture was diluted with water andextracted with DCM. The organic extract was dried over anhydrous MgSO₄,filtered and the filtrate was concentrated to give4-(((3S,4S)-3-(azidomethyl)-4-((5-chloropyridin-2-yl)thio)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile.MS (m/z) 538.1 (M+H⁺). The residue was dissolved in DMF (5 mL), sodiumazide (100 mg, 1.5 mmol) was added, and the reaction mixture was stirredat 80° C. for 40 min. The reaction mixture was cooled to rt, dilutedwith water and extracted with EtOAc. The organic extract was washed withwater, dried over anhydrous MgSO₄, filtered and the filtrate wasconcentrated. The crude product was purified by flash columnchromatography (SiO₂) eluting with a gradient of 0-25% EtOAc in hexanes.The product fractions were pooled and concentrated to give the titlecompound as a colorless wax (115 mg, 39% yield). MS (m/z) 485.1 (M+H⁺).

Step 6:4-(((3S,4S)-3-(aminomethyl)-4-((5-chloropyridin-2-yl)thio)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile

To a solution of4-(((3S,4S)-3-(azidomethyl)-4-((5-chloropyridin-2-yl)thio)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile(115 mg, 0.28 mmol) in THE (4 mL) was added 1.0 M trimethylphosphine inTHE (0.47 mL, 0.47 mmol) and the reaction mixture was stirred at rtovernight. The mixture was loaded onto an SCX cartridge, washed withmethanol, and eluted with 2 M NH₃ in methanol solution. The NH₃ solutionwas collected and concentrated to give the title compound as a colorlesswax (92 mg, 85% yield). MS (m/z) 459.1 (M+H⁺).

Step 7: tert-butyl(((3S,4S)-1-((2-chloro-4-cyanophenyl)sulfonyl)-4-((5-chloropyridin-2-yl)thio)-3-hydroxypyrrolidin-3-yl)methyl)carbamate

To a solution of4-(((3S,4S)-3-(aminomethyl)-4-((5-chloropyridin-2-yl)thio)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile(92 mg, 0.20 mmol) in THE (4 mL) was added Boc₂O (0.06 mL, 0.26 mmol),followed by Et₃N (0.056 mL, 0.401 mmol). The reaction mixture wasstirred at rt for 30 min. The mixture was diluted with water andextracted with EtOAc. The organic extract was dried over anhydrousMgSO₄, filtered and the filtrate was concentrated. The crude product waspurified by flash column chromatography (SiO₂) eluting with a gradientof 0-30% EtOAc in hexanes. The product fractions were pooled andconcentrated to give the title compound as a colorless semi-solid (75mg. 67% yield). MS (m/z) 559.2 (M+H⁺).

Step 8: tert-butyl(((3S,4S)-1-((2-chloro-4-cyanophenyl)sulfonyl)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxypyrrolidin-3-yl)methyl)carbamate

A mixture of tert-butyl(((3S,4S)-1-((2-chloro-4-cyanophenyl)sulfonyl)-4-((5-chloropyridin-2-yl)thio)-3-hydroxypyrrolidin-3-yl)methyl)carbamate(75 mg, 0.13 mmol) and m-CPBA (77 mg, 0.34 mmol) in DCM (4 mL) wasstirred at rt for 3 h. The mixture was quenched with 10% Na₂S₂SO₃ (aq)and extracted with EtOAc. The organic layer was separated, washed withsaturated NaHCO₃ (aq), dried over anhydrous MgSO₄, filtered and thefiltrate was concentrated. The crude product was purified by flashcolumn chromatography (SiO₂) eluting with a gradient of 0-35% EtOAc inhexanes. The product fractions were pooled and concentrated to give thetitle compound as colorless semi-solid (78 mg, 98% yield). MS (m/z)491.1 (M+H⁺-Boc).

Step 9:4-(((3S,4S)-3-(aminomethyl)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile

A mixture of tert-butyl(((3S,4S)-1-((2-chloro-4-cyanophenyl)sulfonyl)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxypyrrolidin-3-yl)methyl)carbamate(78 mg, 0.132 mmol) and TFA (0.30 mL, 4.0 mmol) in DCM (1.0 mL) wasstirred at rt for 30 min. The mixture was concentrated and the residuewas diluted with water. The resulting solution was basified withsaturated NaHCO₃ (aq) and a white solid precipitated. The solid wasfiltered, washed with water, and dried to give the title compound aswhite solid (37 mg, 37% yield). ¹H NMR (400 MHz, DMSO-d₆) δ: 8.90 (d,J=2.0 Hz, 1H), 8.31-8.40 (m, 2H), 8.00-8.17 (m, 3H), 4.29 (d, J=5.5 Hz,1H), 3.91 (dd, J=11.8, 7.3 Hz, 1H), 3.70 (d, J=11.8 Hz, 1H), 3.58 (d,J=10.3 Hz, 1H), 3.43 (d, J=10.0 Hz, 1H, partially hidden by solventpeak), 2.83-2.98 (m, 2H). MS (m/z) 491.3 (M+H⁺).

The following compounds were prepared using procedures analogous tothose described in Example 121 using appropriately substituted startingmaterials. As is appreciated by those skilled in the art, theseanalogous examples may involve variations in general reactionconditions.

MS (m/z) Ex. Name Structure (M + H⁺) ¹H NMR 122 4-(((3R,4S)-3-(aminomethyl)-4- ((4-chlorophenyl) sulfonyl)-3- hydroxypyrrolidin-1-yl)sulfonyl)-3- chlorobenzonitrile

490.1 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.34 (s, 1H), 8.11 (d, J = 8.3 Hz,1H), 8.01-8.06 (m, 1H), 7.87 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 8.5 Hz,2H), 4.26 (t, J = 8.2 Hz, 1H), 3.82 (t, J = 9.0 Hz, 1H), 3.69-3.76 (m,1H), 3.50 (d, J = 9.8 Hz, 1H), 3.27-3.38 (1H, hidden by solvent peak),2.74-2.86 (m, 2H) 123 4-(((3S,4S)-3- (aminomethyl)- 4-((4- chlorophenyl)sulfonyl)-3- hydroxypyrrolidin- 1-yl)sulfonyl)-3- chlorobenzonitrile

489.9 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.39 (s, 1H), 8.09-8.15 (m, 2H), 7.83(s, 4H), 7.25 (br s, 2H), 6.51 (br s, 1H), 4.25 (d, J = 6.3 Hz, 1H),3.86 (dd, J = 11.9, 7.2 Hz, 1H), 3.69 (d, J = 10.3 Hz, 1H), 3.56-3.62(m, 1H), 3.45 (d, J = 11.8 Hz, 1H), 3.22-3.29 (m, 2H) 124 3-chloro-4-(((3S,4S)-4-((4- chlorophenyl) sulfonyl)-3- hydroxy-3- ((methylamino)methyl)pyrrolidin- 1-yl)sulfonyl) benzonitrile

504.0 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.37 (s, 1H), 8.04-8.18 (m, 2H),7.75-7.89 (m, 4H), 4.14 (d, J = 7.0 Hz, 1H), 3.82 (dd, J = 11.7, 7.4 Hz,1H), 3.66 (d, J = 10.3 Hz, 1H), 3.54 (d, J = 11.8 Hz, 1H), 3.46 (d, J =9.8 Hz, 1H),2.87- 3.04 (m, 2H), 2.31 (s, 3H) 125 4-(((3R,4S)-3-(aminomethyl)-4- ((5-chloropyridin- 2-yl)sulfonyl)-3- hydroxypyrrolidin-1-yl)sulfonyl)-3- chlorobenzonitrile

491.1 ¹H NMR (400 MHz, CD₃OD) 8: 8.78 (d, J = 2.0 Hz, 1H), 8.18- 8.25(m, 2H), 8.07-8.14 (m, 2H), 7.92 (dd, J = 8.2, 1.6 Hz, 1H), 4.55 (t, J =8.2 Hz, 1H), 4.23 (dd, J = 11.1, 7.8 Hz, 1H), 4.00 (dd, J = 11.1,8.8 Hz,1H), 3.66-3.77 (m, 2H), 3.55 (d, J = 13.4 Hz, 1H), 3.22 (d, J = 13.4 Hz,1H) 126 4-(((3S,4S)-3- (aminomethyl)-4- ((4-chlorophenyl) sulfonyl)-3-hydroxypyrrolidin- 1-yl)sulfonyl) benzonitrile

456.4 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.16 (d, J = 8.0 Hz, 2H), 7.96 (d, J= 8.0 Hz, 2H), 7.76-7.84 (m, 4H), 4.06 (d, J = 6.8 Hz, 1H), 3.62 (dd, J= 11.8, 7.5 Hz, 1H), 3.45 (d, J = 10.3 Hz, 1H), 3.25- 3.38 (m, 2H,partially hidden by solvent peak), 2.98 (d, J = 13.6 Hz, 1H), 2.82 (d, J= 13.6 Hz, 1H) 127 4-(((3R,4S)-3- (aminomethyl)-4- ((4-chlorophenyl)sulfonyl)-3- hydroxypyrrolidin- 1-yl)sulfonyl) benzonitrile

456.3 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.09 (d, J = 8.0 Hz, 2H), 7.95 (d, J= 8.3 Hz, 2H), 7.81 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 8.3 Hz, 2H), 5.29(br s, 1H), 4.11 (t, J = 7.9 Hz, 1H), 3.58 (d, J = 7.8 Hz, 2H), 3.38 (d,J = 10.3 Hz, 1H), 3.14 (d, J = 10.3 Hz, 1H), 2.57-2.64 (m, 2H, partiallyhidden by solvent peak) 128 3-chloro-4- (((3R,4S)-4-((4- chlorophenyl)sulfonyl)-3- hydroxy- 3-(((2,2,2- trifluoroethyl) amino)methyl)pyrrolidin-1- yl)sulfonyl)benzo nitrile

572.1 ¹H NMR (400 MHz, DMSO-d₆) δ: 8.37 (s, 1H), 8.11-8.18 (m, 1H),8.04-8.10 (m, 1H), 7.82-7.90 (m, 2H). 7.74-7.82 (m, 2H), 5.79 (s, 1H),4.14 (d, J = 5.5 Hz, 1H), 3.82 (dd, J = 11.5, 7.5 Hz, 1H), 3.67 (d, J =10.0 Hz, 1H), 3.55 (d J = 11.5 Hz, 1H), 3.45 (d, J = 10.3 Hz, 1H),3.19-3.27 (m, 2H, partially hidden by solvent peak), 3.10-3.17 (m, 1H),2.97-3.05 (m, 1H), 2.39 (br s, 1H)

Example 1293-chloro-4-(((4S,5R)-4-((5-chloropyridin-2-yl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decan-2-yl)sulfonyl)benzonitrile,Hydrochloride

Step 1: (R)-tert-butyl3-((5-chloropyridin-2-yl)thio)-4-methylenepyrrolidine-1-carboxylate

(S)-tert-butyl 3-hydroxy-4-methylenepyrrolidine-1-carboxylate (10 g, 50mmol) was dissolved in CHCl₃ (100 mL), Et₃N (28 mL, 200 mmol) was addedand the mixture was sparged with nitrogen and cooled in an ice waterbath. MsCl (4.30 mL, 55.2 mmol) was added dropwise and additional MsClwas added in 3 increments (0.43 mL, 5.5 mmol each) to drive the reactionto completion. 5-chloropyridine-2-thiol (18 g, 120 mmol) was added tothe reaction, the ice bath removed, and the reaction allowed to warm tort with stirring overnight. The resulting clear orange solution waswashed with water (150 mL) and the organic layer separated. The aqueousphase was extracted a second time with CHCl₃ (30 mL). The organicextracts were combined, dried over Na₂SO₄, filtered and evaporated. Thecrude product was purified by chromatography (SiO₂) eluting with agradient of 0-5% EtOAc in hexanes. The product fractions were pooled andconcentrated under reduced pressure to give the title compound as aviscous light yellow oil (12.0 g, 73% yield). MS (m/z) 271.1(M+H⁺-t-Bu).

Step 2: (3S,4S)-tert-butyl4-((5-chloropyridin-2-yl)thio)-3-hydroxy-3-(hydroxymethyl)pyrrolidine-1-carboxylate

(R)-tert-butyl3-((5-chloropyridin-2-yl)thio)-4-methylenepyrrolidine-1-carboxylate(11.2 g, 34.3 mmol) and NMO (6.02 g, 51.4 mmol) were mixed in THE (110mL) and OsO₄ (2.5 wt % in t-BuOH, 12.9 mL, 1.03 mmol) was added. Thereaction mixture was stirred at rt and charged with additional NMO(2×1.94 g, 2×16.6 mmol) over 3 h to drive the reaction to completion.The reaction was quenched with sat NaHSO₃ (aq) (70 mL) and extractedwith DCM (3×25 mL). The DCM extracts were combined, dried over Na₂SO₄,filtered, and evaporated under reduced pressure. The crude product waspurified by flash column chromatography (SiO₂) eluting with a gradientof 0-45% EtOAc in hexanes. The product fractions were pooled andconcentrated under reduced pressure to give an unseparable mixture ofthe cis and trans isomers of the title compound as a white solid (6.21g, 50% yield). MS (m/z) 305.1 (M+H⁺-t-Bu). The trans isomer was removedafter subsequent transformations.

Step 3: (3S,4S)-tert-butyl4-((5-chloropyridin-2-yl)thio)-3-hydroxy-3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate

(3S,4S)-tert-butyl4-((5-chloropyridin-2-yl)thio)-3-hydroxy-3-(hydroxymethyl)pyrrolidine-1-carboxylate(2 g, 5.5 mmol) was dissolved in DCM (28 mL), Et₃N (1.2 mL, 8.3 mmol)was added and the mixture was cooled to −20° C. (internal thermocouple)with a dry ice/IPA bath. MsCl (0.46 mL, 6.0 mmol) was added to themixture and was stirred until the reaction was complete. The reactionmixture was poured into water, the DCM layer was separated and theaqueous layer was extracted with DCM (2×20 mL). The organic extractswere combined, dried over Na₂SO₄, filtered and evaporated under reducedpressure to give a mixture of the cis and trans isomers of the titlecompound as an ivory solid (2.47 g, 102% yield). MS (m/z) 383.2(M+H⁺-t-Bu).

Step 4: (3S,4S)-tert-butyl3-(azidomethyl)-4-((5-chloropyridin-2-yl)thio)-3-hydroxypyrrolidine-1-carboxylate

(3S,4S)-tert-butyl4-((5-chloropyridin-2-yl)thio)-3-hydroxy-3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (2.47 g, 5.6 mmol) was mixed with NaN₃ (1.1 g,17 mmol) in dry DMF (28 mL) and warmed to 80° C. and stirred for 4 h.The reaction mixture was cooled, partitioned between water (1 L) andEtOAc and the water layer removed. The organic layer was washed withwater (3×), dried with Na₂SO₄, filtered and evaporated. The crudeproduct was purified by chromatography (SiO₂) eluting with a gradient of0-25% EtOAc in hexanes. The product fractions were pooled andconcentrated to give a mixture of the cis and trans isomers of the titlecompound (617 mg, 28% yield). MS (m/z) 330.1 (M+H⁺-t-Bu).

Step 5: (3R,4S)-tert-butyl3-(aminomethyl)-4-((5-chloropyridin-2-yl)thio)-3-hydroxypyrrolidine-1-carboxylate

(3S,4S)-tert-butyl3-(azidomethyl)-4-((5-chloropyridin-2-yl)thio)-3-hydroxypyrrolidine-1-carboxylate(7.55 g, 19.6 mmol) was dissolved in THE (100 mL) and water (7 mL, 390mmol) was added. After sparging the mixture with nitrogen, under asealed nitrogen atmosphere, Me₃P (1 M in THF) (29.3 mL, 29.3 mmol) wasadded and the reaction mixture was stirred at rt for 20 min. The mixturewas poured into water and extracted several times with DCM. The organicextracts were combined, dried over Na₂SO₄, filtered and concentrated.The crude product was purified by flash column chromatography (SiO₂)eluting with a gradient of 0-10% MeOH:Conc. NH₄OH (9:1) in DCM. Theproduct fractions were pooled and concentrated to give a mixture of thecis and trans isomers of the title compound as a fluffy white-yellowsolid (6.42 g, 91% yield). MS (m/z) 360.4 (M+H⁺).

Step 6: (4S,5R)-tert-butyl4-((5-chloropyridin-2-yl)thio)-8-oxo-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxylate

(3R,4S)-tert-butyl3-(aminomethyl)-4-((5-chloropyridin-2-yl)thio)-3-hydroxypyrrolidine-1-carboxylate(1.5 g, 4.2 mmol) was dissolved in DCM (30 mL) and Et₃N (1.2 mL, 8.3mmol) was added followed by a portionwise addition of 2-chloroacetylchloride (0.348 mL, 4.38 mmol). Two additional increments of2-chloroacetyl chloride (45 L, 0.57 mmol each) were added to drive thereaction to completion. The reaction mixture was washed with water (40mL,) dried over Na₂SO₄, filtered and concentrated. The residue wasdissolved in dry THE (30 mL) at rt, t-BuOK (0.56 g, 5.0 mmol) was added,and the mixture was stirred for 5 min. The reaction mixture was thenpartitioned between DCM and sat'd NaHCO₃ (aq). The organic layer wasseparated and the aqueous phase was extracted with additional DCM (3×15mL). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by chromatography (SiO₂)eluting with a gradient of 0-85% EtOAc in hexanes and the productfractions were pooled and concentrated to give a mixture of the cis andtrans isomers of the title compound (1.02 g, 61% yield). MS (m/z) 344.0(M+H⁺-t-Bu).

Step 7:3-chloro-4-(((4S,5R)-4-((5-chloropyridin-2-yl)thio)-8-oxo-6-oxa-2,9-diazaspiro[4.5]decan-2-yl)sulfonyl)benzonitrile

(4S,5R)-tert-butyl4-((5-chloropyridin-2-yl)thio)-8-oxo-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxylate(1.02 g, 2.55 mmol) was dissolved in TFA (10 mL, 130 mmol). Checkedreaction by TLC and it was found to be complete. Evaporated reaction todryness and reevaporated with DCM (3×) to give the deprotectedpyrrolidine. The intermediate was dissolved in DCM (30 mL) and Et₃N (1.8mL, 13 mmol) was added, followed by 2-chloro-4-cyanobenzene-1-sulfonylchloride (0.63 g, 2.7 mmol). TLC after addition shows reaction iscomplete. The mixture was evaporated to dryness and the crude productpurified by chromatography (SiO₂) eluting with a gradient of 0-95% EtOAcin hexanes. The product fractions were pooled and evaporated to give amixture of the cis and trans isomers of the title compound as a whitefoam (1.21 g, 95% yield). MS (m/z) 498.9 (M+H⁺).

Step 8:3-chloro-4-(((4S,5R)-4-((5-chloropyridin-2-yl)sulfonyl)-8-oxo-6-oxa-2,9-diazaspiro[4.5]decan-2-yl)sulfonyl)benzonitrile

3-chloro-4-(((4S,5R)-4-((5-chloropyridin-2-yl)thio)-8-oxo-6-oxa-2,9-diazaspiro[4.5]decan-2-yl)sulfonyl)benzonitrile(1.21 g, 2.42 mmol) was dissolved in DCM (12 mL), m-CPBA (1.36 g, 6.06mmol) was added and the reaction mixture was stirred at rt overnight.The reaction mixture was diluted with DCM, washed with NaHSO₃ (aq) andthe DCM layer separated. The aqueous layer was extracted with DCM (2×).The DCM layers were combined, washed with NaHCO₃ (aq), dried overNa₂SO₄, filtered and evaporated to give a crude mixture of the cis andtrans isomers of the title compound (1.25 g, 97% yield). The crudecis/trans mixture (850 mg) was separated by reverse phase HPLC (SunfireC18 column, eluting with 35% CH₃CN/H₂O (0.1% TFA) isocratically). Theseparated isomer fractions were each pooled, treated with DCM and washedwith NaHCO₃ (aq). The organic layers were dried over Na₂SO₄, filteredand concentrated to give the individual cis and trans isomers of thetitle compound. Cis-isomer: first eluant, (355 mg), ¹H NMR (400 MHz,DMSO-d₆) δ: 8.83 (s, 1H), 8.38 (s, 1H), 8.28 (br d, J=8.5 Hz, 1H), 8.20(br d, J=2.2 Hz, 1H), 8.15 (d, J=8.4 Hz, 1H), 8.07 (d, J=8.2 Hz, 1H),8.03 (d, J=8.5 Hz, 1H), 4.67 (t, J=7.8 Hz, 1H), 4.11 (dd, J=11.0, 6.9Hz, 1H), 3.91-3.96 (m, 1H), 3.82 (s, 1H), 3.73-3.78 (m, 1H), 3.70-3.81(m, 3H), 3.48 (d, J=10.9 Hz, 1H). MS (m/z) 530.9 (M+H⁺). Trans-isomer:second eluant, (339 mg), ¹H NMR (400 MHz, DMSO-d₆) δ: 8.86 (s, 1H), 8.37(s, 1H), 8.34 (br d, J=8.4 Hz, 1H), 8.12-8.15 (m, 1H), 8.08-8.11 (m,1H), 8.06 (s, 1H), 7.93 (br s, 1H), 4.83-4.86 (m, 1H), 4.24 (d, J=17.2Hz, 1H), 4.02 (d, J=17.2 Hz, 1H), 3.93-3.97 (m, 2H), 3.63 (br d, J=3.5Hz, 2H), 3.58-3.62 (m, 1H), 3.47-3.51 (m, 1H). MS (m/z) 530.9 (M+H⁺).

Step 9:3-chloro-4-(((4S,5R)-4-((5-chloropyridin-2-yl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decan-2-yl)sulfonyl)benzonitrile,Hydrochloride

3-chloro-4-(((4S,5R)-4-((5-chloropyridin-2-yl)sulfonyl)-8-oxo-6-oxa-2,9-diazaspiro[4.5]decan-2-yl)sulfonyl)benzonitrile(65 mg, 0.12 mmol) was dissolved in dry THE (3 mL). The solution wassparged with nitrogen and cooled in an ice/IPA bath followed by theaddition of borane THE complex (0.73 mL, 0.73 mmol). The reactionmixture was stirred for 2 h and then quenched with a dropwise additionof MeOH (3 mL). The mixture was concentrated, dissolved in MeOH, treateddropwise with 12 N HCl (aq) and stirred. The reaction mixture was thenconcentrated and DCM (20 mL) was added to the residue followed by Et₃N(0.085 mL, 0.61 mmol). Boc-anhydride (43 μl, 0.18 mmol) was added to themixture in increments and stirred until the reaction was complete. Thereaction mixture was evaporated and the residue was purified bychromatography (SiO₂) eluting with a gradient of 0-55% EtOAc in hexanes.The product fractions were pooled and concentrated and the residue wastreated with 4 M HCl in dioxane (5 mL), stirred at rt for 40 min andconcentrated. The residue was lyophilized in MeCN/water (1:1) to givethe title compound as an ivory solid (28 mg, 41% yield). ¹H NMR (400MHz, DMSO-d₆) δ: 9.63 (br s, 1H), 9.26 (br s, 1H), 8.87 (s, 1H), 8.37(s, 1H), 8.29 (d, J=8.3 Hz, 1H), 8.05-8.18 (m, 3H), 4.73 (t, J=8.9 Hz,1H), 4.27 (d, J=12.0 Hz, 1H), 4.10 (t, J=9.4 Hz, 1H), 3.87 (t, J=9.5 Hz,1H), 3.37-3.75 (m, 6H, partially hidden by solvent peak), 3.13 (d,J=12.5 Hz, 1H). MS (m/z) 516.9 (M+H⁺).

Example 130—Capsule Composition

An oral dosage form for administering the present invention is producedby filing a standard two piece hard gelatin capsule with the ingredientsin the proportions shown in Table 1, below.

TABLE 1 INGREDIENTS AMOUNTS3-chloro-4-(((3R,4S)-4-((5-chloropyridin-2-yl)sulfonyl)-3- 7 mghydroxy-3-(hydroxymethyl)pyrrolidin-1- yl)sulfonyl)benzonitrile(Compound of Example 1) Lactose 53 mg Talc 16 mg Magnesium Stearate 4 mg

Example 131—Injectable Parenteral Composition

An injectable form for administering the present invention is producedby stirring 1.7% by weight of3-chloro-4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile(Compound of Example 2) in 10% by volume propylene glycol in water.

Example 132 Tablet Composition

The sucrose, calcium sulfate dihydrate and a TRPV4 inhibitor as shown inTable 2 below, are mixed and granulated in the proportions shown with a10% gelatin solution. The wet granules are screened, dried, mixed withthe starch, talc and stearic acid, screened and compressed into atablet.

TABLE 2 INGREDIENTS AMOUNTS4-(((3S,4S)-1-((2-chloro-4-cyanophenyl)sulfonyl)-4- 12 mghydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2- fluorobenzonitrile(Compound of Example 3) calcium sulfate dihydrate 30 mg sucrose 4 mgstarch 2 mg talc 1 mg stearic acid 0.5 mg

While the preferred embodiments of the invention are illustrated by theabove, it is to be understood that the invention is not limited to theprecise instructions herein disclosed and that the right to allmodifications coming within the scope of the following claims isreserved.

1. A compound according to Formula I:

wherein: R¹ is selected from: aryl, aryl substituted from 1 to 4 timesby R^(a), heteroaryl, heteroaryl substituted from 1 to 4 times by R^(a),bicycloheteroaryl, and bicycloheteroaryl substituted from 1 to 4 timesby R^(a); R² is selected from: aryl, aryl substituted from 1 to 4 timesby R^(b), heteroaryl, heteroaryl substituted from 1 to 4 times by R^(b),bicycloheteroaryl, and bicycloheteroaryl substituted from 1 to 4 timesby R^(b), and Y¹ is selected from: C₁₋₆alkyl, and C₁₋₆alkyl substitutedwith from: 1 to 9 substitutents independently selected from: fluoro,chloro, bromo, iodo, OC₁₋₆alkyl, —OC₁₋₆alkyl substituted with from 1 to6 substituents independently selected from: fluoro, oxo, —OH, —COOH,—NH₂, and —CN, mercapto, —S(O)H, —S(O)₂H, oxo, hydroxy, amino,NHR^(x11), where R^(x11) is selected from C₁₋₆alkyl, and C₁₋₆alkylsubstituted with from 1 to 6 substituents independently selected from:fluoro, oxo, —OH, —COOH, —NH₂, —CN, —OC₁₋₅alkyl, —OC₁₋₅alkyl substitutedfrom 1 to 6 times by fluoro and —NH₂, NR^(x12)R^(x13), where R^(x12) andR^(x13) are each independently selected from C₁₋₆alkyl, and C₁₋₆alkylsubstituted with from 1 to 6 substituents independently selected from:fluoro, oxo, —OH, —COOH, —NH₂, and —CN, —C(O)OH, —C(O)NH₂, aryl, Oaryl,heteroaryl, Oheteroaryl, —S(O)₂NH₂, —NHS(O)₂H, nitro, and cyano, or Y¹is taken together with the adjacent —OH to form a heterocyclic ringselected from: morpholinyl, morpholinyl substituted by —CH₃, andoxazolidin-2-one; each R^(a) is independently selected from: fluoro,chloro, bromo, iodo, —OH, C₁₋₆alkyl, C₁₋₆alkyl substituted with from 1to 5 substituents independently selected from: fluoro, chloro, bromo,iodo, C₁₋₄alkyloxy, —OH, C₁₋₄alkyl, phenyl, oxo, —COOH, —NO₂, —NH₂ and—CN, cyano, —OC₁₋₆alkyl, —OC₁₋₆alkyl substituted with from 1 to 5substituents independently selected from: fluoro, chloro, bromo, iodo,C₁₋₄alkyloxy, —OH, C₁₋₄alkyl, phenyl, oxo, —COOH, —NO₂, —NH₂ and —CN,—Ophenyl, —C(O)OC₁₋₆alkyl, —C(O)OC₁₋₆alkyl substituted 1 to 5 times byfluoro, and —Ocycloalkyl; and each R^(b) is independently selected from:fluoro, chloro, bromo, iodo, —OH, C₁₋₆alkyl, C₁₋₆alkyl substituted withfrom 1 to 5 substituents independently selected from: fluoro, chloro,bromo, iodo, C₁₋₄alkyloxy, —OH, C₁₋₄alkyl, phenyl, oxo, —COOH, —NO₂,—NH₂ and —CN, cyano, —OC₁₋₆alkyl, —OC₁₋₆alkyl substituted with from 1 to5 substituents independently selected from: fluoro, chloro, bromo, iodo,C₁₋₄alkyloxy, —OH, C₁₋₄alkyl, phenyl, oxo, —COOH, —NO₂, —NH₂ and —CN,—Ocycloalkyl, phenyl, —C≡C—Si(CH₃)₃, and C≡C-cycloalkyl; or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1represented by the following Formula (II):

wherein: R²¹ is selected from: aryl, aryl substituted from 1 to 3 timesby R^(a2), heteroaryl, heteroaryl substituted from 1 to 3 times byR^(a2), bicycloheteroaryl, and bicycloheteroaryl substituted from 1 to 3times by R^(b2), R²² is selected from: aryl, aryl substituted from 1 to4 times by R^(b2), heteroaryl, and heteroaryl substituted from 1 to 3times by R^(b2), and Y²¹ is selected from: C₁₋₆alkyl, and C₁₋₆alkylsubstituted with from: 1 to 9 substitutents independently selected from:fluoro, chloro, —OC₁₋₆alkyl, —OC₁₋₆alkyl substituted with from 1 to 6substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH₂,and —CN, oxo, hydroxy, amino, —NHR^(x21), where R^(x21) is selected fromC₁₋₅alkyl, and C₁₋₅alkyl substituted with from 1 to 6 substituentsindependently selected from: fluoro, oxo, —OH, —COOH, —NH₂, and —CN,—C(O)OH, —C(O)NH₂, nitro, and cyano, or Y²¹ is taken together with theadjacent —OH to form morpholinyl, and morpholinyl substituted by —CH₃;each R^(a2) is independently selected from: fluoro, chloro, bromo, iodo,—OH, C₁₋₆alkyl, C₁₋₆alkyl substituted with from 1 to 5 substituentsindependently selected from: fluoro, chloro, bromo, iodo, C₁₋₄alkyloxy,—OH, C₁₋₄alkyl, phenyl, oxo, —COOH, —NO₂, —NH₂ and —CN, cyano,—OC₁₋₆alkyl, —OC₁₋₆alkyl substituted with from 1 to 5 substituentsindependently selected from: fluoro, chloro, bromo, iodo, C₁₋₄alkyloxy,—OH, C₁₋₄alkyl, phenyl, oxo, —COOH, —NO₂, —NH₂ and —CN, —Ophenyl,—C(O)OC₁₋₅alkyl, —C(O)OC₁₋₅alkyl substituted 1 to 5 times by fluoro, and—Ocycloalkyl; and each R^(b2) is independently selected from: fluoro,chloro, bromo, —OH, C₁₋₆alkyl, C₁₋₆alkyl substituted with from 1 to 5substituents independently selected from: fluoro, chloro, bromo, iodo,C₁₋₄alkyloxy, —OH, C₁₋₄alkyl, phenyl, oxo, —COOH, —NO₂, —NH₂ and —CN,cyano, —OC₁₋₆alkyl, —OC₁₋₆alkyl substituted with from 1 to 5substituents independently selected from: fluoro, chloro, bromo, iodo,C₁₋₄alkyloxy, —OH, C₁₋₄alkyl, phenyl, oxo, —COOH, —NO₂, —NH₂ and —CN,—Ocycloalkyl, and phenyl; or a pharmaceutically acceptable salt thereof.3. The compound of claim 1 represented by the following Formula (III):

wherein: R³¹ is selected from: phenyl, phenyl substituted from 1 to 3times by R^(a3), thiazole, thiazole substituted from 1 to 3 times byR^(a3), pyrimidine, pyrimidine substituted from 1 to 3 times by R^(a3),pyridine, and pyridine substituted from 1 to 3 times by R^(a3); R³² isselected from: phenyl, phenyl substituted from 1 to 3 times by R^(b3),pyridine, and pyridine substituted from 1 to 3 times by R^(b3); and Y³¹is selected from: —CH₂OH, —CH(OH)CH₃, —CH(OH)CH₂CH₃, —C(OH)(CH₃)₂,—CH₂NH₂, —CH₂NHR^(x30), and —CH(NH₂)CH₃, or Y³¹ is taken together withthe adjacent —OH to form morpholinyl, where each R^(x30) isindependently selected from: C₁₋₆alkyl, and C₁₋₆alkyl substituted withfrom 1 to 6 substituents independently selected from: fluoro, oxo, —OH,—COOH, —NH₂, and —CN; each R^(a3) is independently selected from:fluoro, chloro, bromo, —OH, C₁₋₆alkyl, cyano, —CF₃, —C₁₋₅alkylCF₃,—CHF₂, —CH₂F, —OC₁₋₅alkyl, —OCF₃, —OC₁₋₅alkylCF₃, —Ophenyl, —Obenzyl,—C₁₋₅alkylCN, —C(O)OC₁₋₅alkyl, —C(O)OH, and —Ocycloalkyl; and eachR^(b3) is independently selected from: fluoro, chloro, bromo, —OH,C₁₋₆alkyl, cyano, —CF₃, —C₁₋₅alkylCF₃, —CHF₂, —CH₂F, —OC₁₋₅alkyl, —OCF₃,—OC₁₋₅alkylCF₃, —C(O)CH₃, —OCHF₂, —Ocyclopropyl, and phenyl; or apharmaceutically acceptable salt thereof.
 4. The compound of claim 1represented by the following Formula (IV):

wherein: R⁴¹ is selected from: phenyl, phenyl substituted from 1 to 3times by R^(a4), thiazole, thiazole substituted from 1 to 3 times byR^(a3), pyrimidine, pyrimidine substituted from 1 to 3 times by R^(a3),pyridine, and pyridine substituted from 1 to 3 times by R^(a3); R⁴² isselected from: phenyl, phenyl substituted from 1 to 3 times by R^(b4),pyridine, and pyridine substituted from 1 to 3 times by R^(b4); and Y⁴¹is selected from: —CH₂OH, —CH(OH)CH₃, —CH₂NH₂, and —CH₂NHR^(x40), or Y³¹is taken together with the adjacent —OH to form morpholinyl, where eachR^(x40) is independently selected from: C₁₋₆alkyl, and C₁₋₆alkylsubstituted with from 1 to 6 substituents independently selected from:fluoro, oxo, —OH, —COOH, —NH₂, and —CN; each R^(a4) is independentlyselected from: fluoro, chloro, bromo, —OH, C₁₋₆alkyl, cyano, —CF₃,—C₁₋₅alkylCF₃, —CHF₂, —CH₂F, —OC₁₋₅alkyl, —C(O)OC₁₋₅alkyl, and —C(O)OH;and each R^(b4) is independently selected from: fluoro, chloro, bromo,—OH, C₁₋₆alkyl, cyano, —CF₃, —C₁₋₅alkylCF₃, —CHF₂, —CH₂F, —OC₁₋₅alkyl,—OCF₃, —OC₁₋₅alkylCF₃, —C(O)CH₃, —OCHF₂, Ocyclopropyl; or apharmaceutically acceptable salt thereof.
 5. A compound of claim 1selected from:3-chloro-4-(((3R,4S)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;3-chloro-4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;4-(((3S,4S)-1-((2-chloro-4-cyanophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;4-(((3S,4S)-1-((2-chlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;4-(((3S,4S)-1-((2-chloro-4-fluorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;4-(((3S,4S)-1-((2-chloro-4-methylphenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;4-(((3S,4S)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;4-(((3S,4S)-1-((2-chloro-4-(trifluoromethoxy)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;4-(((3S,4S)-1-((2,4-dichloro-5-fluorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;4-(((3S,4R)-1-((2-chloro-4-cyanophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;4-(((3S,4R)-1-((2-chlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;4-(((3S,4R)-1-((2-chloro-4-fluorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;4-(((3S,4R)-1-((2-chloro-4-methylphenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;4-(((3S,4R)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;4-(((3S,4R)-1-((2-chloro-4-(trifluoromethoxy)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;4-(((3S,4R)-1-((2,4-dichloro-5-fluorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;5-chloro-2-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;(3R,4S)-4-((4-chlorophenyl)sulfonyl)-1-((2,4-dichlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-(trifluoromethyl)benzonitrile;4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-methylbenzonitrile;4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-fluorobenzonitrile;4-(((3S,4R)-1-((2-bromo-4-fluorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;3-chloro-4-(((3S,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;4-(((3S,4S)-4-((4-bromophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile;4-(((3S,4R)-1-((4-chloro-2-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;3-chloro-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((6-(trifluoromethyl)pyridin-3-yl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((6-(trifluoromethyl)pyridin-3-yl)sulfonyl)pyrrolidin-1-yl)sulfonyl)-3-(trifluoromethyl)benzonitrile;4-(((3S,4R)-4-hydroxy-4-(hydroxymethyl)-1-((2-methyl-4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;4-(((3S,4R)-1-((4-fluoro-2-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;4-(((3S,4R)-1-((4-bromo-2-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;4-(((3S,4R)-4-hydroxy-4-(hydroxymethyl)-1-((4-methoxy-2-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;4-(((3S,4R)-1-((2-bromo-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;4-(((3S,4R)-1-((2-bromophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;4-(((3S,4R)-1-((4-bromo-2-chlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-methoxybenzonitrile;4-(((3S,4R)-1-((2-fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;(3R,4S)-1-((2-chloro-4-(difluoromethyl)phenyl)sulfonyl)-4-((4-chlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;3-bromo-4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;3-bromo-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((6-(trifluoromethyl)pyridin-3-yl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;5-chloro-2-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((6-(trifluoromethyl)pyridin-3-yl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;4-(((3S,4R)-4-hydroxy-4-(hydroxymethyl)-1-((2-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;4-(((3S,4R)-1-((2-chloro-4-(difluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;(3R,4S)-1-((2-chloro-4-(fluoromethyl)phenyl)sulfonyl)-4-((4-chlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;4-(((3S,4R)-1-((2-chloro-4-(fluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;3-chloro-4-(((3R,4S)-4-((4-cyanophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-ethylbenzonitrile;2-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-(difluoromethyl)benzonitrile;4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-ethoxybenzonitrile;4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-cyclopropoxybenzonitrile;4-(((3S,4R)-1-((4-chloro-2-methoxyphenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;4-(((3S,4R)-1-((4-bromo-2-methoxyphenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;2-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;3-chloro-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;3-(difluoromethyl)-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-1-yl)sulfonyl)-3-methoxybenzonitrile;3-cyclopropoxy-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;4-(((3S,4R)-1-((2-chloro-4-methylphenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;4-(((3S,4R)-1-((2-bromo-4-chlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;4-(((3S,4R)-1-((2-bromo-4-methoxyphenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;3-cyclopropoxy-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((5-(trifluoromethyl)pyridin-2-yl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;4-(((3S,4R)-1-((2-chloro-4-fluorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;4-(((3S,4R)-1-((2,4-dichloro-5-fluorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;methyl4-(((3S,4R)-1-((4-chloro-2-(difluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzimidate;(3R,4S)-1-((4-chloro-2-(difluoromethyl)phenyl)sulfonyl)-4-((4-chlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;2-(5-chloro-2-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)phenyl)acetonitrile;(3R,4S)-4-((4-chlorophenyl)sulfonyl)-1-((2-(difluoromethoxy)pyridin-3-yl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;3-chloro-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-(thiazol-2-ylsulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;2-fluoro-4-(((3S,4R)-1-((2-fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;4-(((3S,4R)-1-((4-cyano-2-methylphenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;2-fluoro-4-(((3S,4R)-4-hydroxy-4-(hydroxymethyl)-1-((2-methyl-4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;2-fluoro-4-(((3S,4R)-4-hydroxy-4-(hydroxymethyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;3-chloro-4-(((3R,4S)-4-((5-chlorothiazol-2-yl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;4-(((3R,4S)-4-((4-bromophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile;4-(((3S,4S)-1-((2,4-dichlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;(3S,4S)-4-((4-chloro-3-fluorophenyl)sulfonyl)-1-((2,4-dichlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;2-(((3S,4S)-4-((3,4-difluorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-5-(trifluoromethyl)benzonitrile;(3S,4S)-4-((4-chloro-3-fluorophenyl)sulfonyl)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;4-(((3S,4S)-1-((2,4-dichlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2,5-difluorobenzonitrile;2-chloro-4-(((3S,4S)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;4-(((3S,4S)-4-((5-bromopyridin-2-yl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile;4-(((3S,4R)-1-((2,4-dichlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;4-(((3S,4R)-1-((2,4-dichlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;5-chloro-2-(((3R,4S)-4-((4-cyanophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;(3R,4S)-1-((2,4-dichlorophenyl)sulfonyl)-4-((3,4-difluorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;4-(((3S,4R)-1-((2,4-dichlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-3-fluorobenzonitrile;4-(((3S,4R)-1-((2,4-dichlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2,6-difluorobenzonitrile;(3R,4S)-4-((4-chloro-3-fluorophenyl)sulfonyl)-1-((2,4-dichlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;4-(((3S,4R)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;4-(((3S,4S)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;4-(((3S,4R)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2,6-difluorobenzonitrile;5-(((3S,4R)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)picolinonitrile;2-(((3R,4S)-4-((3,4-difluorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-5-(trifluoromethyl)benzonitrile;2-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((3,4,5-trifluorophenyl)sulfonyl)pyrrolidin-1-yl)sulfonyl)-5-(trifluoromethyl)benzonitrile;4-(((3S,4R)-1-((2,4-dichlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2,5-difluorobenzonitrile;(3R,4S)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-3-(hydroxymethyl)-4-((4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-3-ol;(3R,4S)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-((4-chlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;(3R,4S)-4-((4-chloro-3-fluorophenyl)sulfonyl)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;(3R,4S)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-((6-chloropyridin-3-yl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;4-(((3S,4R)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-methylbenzonitrile;2-chloro-4-(((3S,4R)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;(3R,4S)-1-((2,4-dichlorophenyl)sulfonyl)-4-((4-fluorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;2-chloro-5-(((3S,4R)-1-((2,4-dichlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;3-chloro-4-(((3R,4S)-4-((4-ethylphenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;3-chloro-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((4-isopropylphenyl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;3-chloro-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((4-propylphenyl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;3-chloro-4-(((3R,4S)-4-((4-chloro-3-fluorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;(3R,4S)-1-((2,4-dichlorophenyl)sulfonyl)-3-(hydroxymethyl)-4-((2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)pyrrolidin-3-ol;3-chloro-4-(((3S,4S)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;3-chloro-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((5-(trifluoromethyl)pyridin-2-yl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;3-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)picolinonitrile;3-chloro-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;4-(((3R,4S)-4-((5-bromopyridin-2-yl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile;(3R,4S)-1-((2,4-dichlorophenyl)sulfonyl)-4-((3,4-dichlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;(3S,4S)-1-((2,4-dichlorophenyl)sulfonyl)-4-((3,4-dichlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;(3R,4S)-1-((2,4-dichlorophenyl)sulfonyl)-3-(hydroxymethyl)-4-((5-(trifluoromethyl)pyridin-2-yl)sulfonyl)pyrrolidin-3-ol;2-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-5-(trifluoromethyl)benzonitrile;(3R,4S)-1-((2,4-dichlorophenyl)sulfonyl)-3-(hydroxymethyl)-4-((6-(trifluoromethyl)pyridin-3-yl)sulfonyl)pyrrolidin-3-ol;3-chloro-4-(((3R,4S)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxy-3-((R)-1-hydroxyethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;3-chloro-4-(((3R,4S)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxy-3-((S)-1-hydroxyethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;4-(((3S,4S)-3-(aminomethyl)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile;4-(((3R,4S)-3-(aminomethyl)-4-((4-chlorophenyl)sulfonyl)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile;4-(((3S,4S)-3-(aminomethyl)-4-((4-chlorophenyl)sulfonyl)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile;3-chloro-4-(((3S,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-((methylamino)methyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;4-(((3R,4S)-3-(aminomethyl)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile;4-(((3S,4S)-3-(aminomethyl)-4-((4-chlorophenyl)sulfonyl)-3-hydroxypyrrolidin-1-yl)sulfonyl)benzonitrile;4-(((3R,4S)-3-(aminomethyl)-4-((4-chlorophenyl)sulfonyl)-3-hydroxypyrrolidin-1-yl)sulfonyl)benzonitrile;3-chloro-4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(((2,2,2-trifluoroethyl)amino)methyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;and3-chloro-4-(((4S,5R)-4-((5-chloropyridin-2-yl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decan-2-yl)sulfonyl)benzonitrile,or a pharmaceutically acceptable salt thereof.
 6. A pharmaceuticalcomposition comprising a compound of Formula (I) according to claim 1 ora pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable excipient.
 7. A method of treating a disease state selectedfrom: atherosclerosis, vasogenic edema, postsurgical abdominal edema,ocular edema, cerebral edema, local and systemic edema, fluid retention,sepsis, hypertension, inflammation, bone related dysfunctions andcongestive heart failure, pulmonary disorders, chronic obstructivepulmonary disorder, ventilator induced lung injury, high altitudeinduced pulmonary edema, acute respiratory distress syndrome, acute lunginjury, pulmonary fibrosis, sinusitis/rhinitis, asthma, COPD, cough,acute cough, sub-acute cough, chronic cough, pulmonary hypertension,overactive bladder, cystitis, pain, motor neuron disorders, genetic gainof function disorders, amyotrophic lateral sclerosis, multiplesclerosis, cardiovascular disease, acute, chronic and polycystic kidneydisease, stroke, hydrocephalus, glaucoma, retinopathy, endometriosis,pre-term labor, dermatitis, pruritus, pruritus in liver disease, ascitesand complications of portal hypertension and liver cirrhosis, diabetes,metabolic disorder, obesity, migraine, Alzheimer's disease,pancreatitis, tumor suppression, immunosuppression, osteoarthritis,crohn's disease, colitis, diarrhea, intestinal irregularity(hyperreactivity/hyporeactivity), fecal incontinence, irritable bowelsyndrome (IBS), constipation, intestinal pain and cramping, celiacdisease, lactose intolerance, and flatulence, in a human in needthereof, which comprises administering to such human a safe andeffective amount of a compound according to Formula (I) of claim 1, or apharmaceutically acceptable salt thereof.
 8. A method according to claim7 wherein the compound or pharmaceutically acceptable salt thereof isadministered orally.
 9. A method according to claim 7 wherein thecompound or pharmaceutically acceptable salt thereof is administeredintravenously.
 10. A method according to claim 7 wherein the compound orpharmaceutically acceptable salt thereof is administered by inhalation.11. (canceled)
 12. A method according to claim 7 wherein the diseasestate is acute lung injury.
 13. (canceled)
 14. A method according toclaim 7 wherein the disease state is heart failure.
 15. A methodaccording to claim 7 wherein the disease state is acute respiratorydistress syndrome.
 16. A method according to claim 7 wherein the diseasestate is cough.
 17. A method according to claim 7 wherein the diseasestate is acute cough.
 18. A method according to claim 7 wherein thedisease state is sub-acute cough.
 19. A method according to claim 7wherein the disease state is chronic cough.
 20. (canceled)
 21. Themethod of inhibiting TRPV4 activity in a human in need thereof, whichcomprises administering to such human a safe and effective amount of acompound according to Formula (I) of any one of claims 1 to 5, or apharmaceutically acceptable salt thereof.
 22. A method of treating adisease state in a human in need thereof according to claim 7, whichcomprises administering to such human a safe and effective amount of a)a compound according to Formula (I), of claim 5 or a pharmaceuticallyacceptable salt thereof; and b) at least one agent selected from thegroup consisting of endothelin receptor antagonists, angiotensinconverting enzyme (ACE) inhibitors, angiotension II receptorantagonists, vasopeptidase inhibitors, vasopressin receptor modulators,diuretics, digoxin, beta blockers, aldosterone antagonists, inotropes,NSAIDS, nitric oxide donors, calcium channel modulators, muscarinicantagonists, steroidal anti-inflammatory drugs, bronchodilators,antihistamines, leukotriene antagonists, HMG-CoA reductase inhibitors,dual non-selective β-adrenoceptor and α1-adrenoceptor antagonists,type-5 phosphodiesterase inhibitors, and renin inhibitors.
 23. A processfor preparing a pharmaceutical composition containing a pharmaceuticallyacceptable excipient and an effective amount of a compound according toFormula (I) of claim 5 or a pharmaceutically acceptable salt thereof,which process comprises bringing the compound of Formula (I) or apharmaceutically acceptable salt thereof into association with apharmaceutically acceptable excipient.
 24. (canceled)
 25. (canceled)